BR112019015406A2 - pharmaceutical compositions for combination therapy - Google Patents
pharmaceutical compositions for combination therapy Download PDFInfo
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- BR112019015406A2 BR112019015406A2 BR112019015406A BR112019015406A BR112019015406A2 BR 112019015406 A2 BR112019015406 A2 BR 112019015406A2 BR 112019015406 A BR112019015406 A BR 112019015406A BR 112019015406 A BR112019015406 A BR 112019015406A BR 112019015406 A2 BR112019015406 A2 BR 112019015406A2
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- fibrosis
- agonist
- ppar
- combination product
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Abstract
a presente invenção se refere a um produto de combinação e seu uso em terapia.the present invention relates to a combination product and its use in therapy.
Description
COMPOSIÇÕES FARMACÊUTICAS PARA TERAPIA DE COMBINAÇÃOPHARMACEUTICAL COMPOSITIONS FOR COMBINATION THERAPY
[0001] A presente invenção se refere a combinações de nitazoxanida (NTZ) ou um derivado da mesma em combinação com um agonista de PPAR para terapia.[0001] The present invention relates to combinations of nitazoxanide (NTZ) or a derivative thereof in combination with a PPAR agonist for therapy.
[0002] [2- [(5-nitro-l,3-tiazol-2il)carbamoil]fenil]etanoato, (ou nitazoxanida, ou NTZ), primeira descrita em 1975 (Rossignol e Cavier, 1975), foi demonstrada como sendo altamente eficaz contra protozoários anaeróbicos, helmintos e um amplo espectro de micróbios incluindo tanto bactérias anaeróbicas quanto aeróbicas (Rossignol e Maisonneuve, 1984; Dubreuil, Houcke et al. , 1996; Megraudd, Occhialini et al. , 1998; Fox e Saravolatz, 2005; Pankuch e Appelbaum, 2006; Finegold, Molitoris et al. , 2009) . A mesma foi primeiramente estudada em humanos para o tratamento de cestodas intestinais (Rossignol e Maisonneuve, 1984) e é atualmente licenciada nos Estados Unidos (Alinia®, Remark laboratories) para o tratamento de diarréia provocada pelos parasitas protozoários Crystosporldium parvum e Giardia intestinalis. NTZ também tem sido amplamente comercializada na América Latina e na índia onde é indicada para tratar um amplo espectro de infecções parasitárias intestinais (Hemphill, Mueller et al. , 2006) . O mecanismo de ação proposto pelo qual a NTZ exerce sua atividade antiparasitária se dá através da inibição de reações de transferência de elétron dependentes de enzima piruvato:ferredoxina oxidorredutase (PFOR) que são essenciais para o metabolismo anaeróbico.(Hoffman, Sisson et al. , 2007) . NTZ também exibiu atividade contra Mycobacterium tuberculosis, que não possui um homólogo de[0002] [2- [(5-nitro-1,3-thiazol-2yl) carbamoyl] phenyl] etanoate, (or nitazoxanide, or NTZ), first described in 1975 (Rossignol and Cavier, 1975), has been demonstrated to be highly effective against anaerobic protozoa, helminths and a broad spectrum of microbes including both anaerobic and aerobic bacteria (Rossignol and Maisonneuve, 1984; Dubreuil, Houcke et al., 1996; Megraudd, Occhialini et al., 1998; Fox and Saravolatz, 2005; Pankuch and Appelbaum, 2006; Finegold, Molitoris et al., 2009). It was first studied in humans for the treatment of intestinal baskets (Rossignol and Maisonneuve, 1984) and is currently licensed in the United States (Alinia®, Remark laboratories) for the treatment of diarrhea caused by the protozoan parasites Crystosporldium parvum and Giardia intestinalis. NTZ has also been widely marketed in Latin America and India where it is indicated to treat a wide range of intestinal parasitic infections (Hemphill, Mueller et al., 2006). The proposed mechanism of action by which NTZ exerts its antiparasitic activity is through the inhibition of pyruvate enzyme-dependent electron transfer reactions: ferredoxin oxidoreductase (PFOR) that are essential for anaerobic metabolism. (Hoffman, Sisson et al., 2007). NTZ also exhibited activity against Mycobacterium tuberculosis, which does not have a
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PFOR, sugerindo assim um mecanismo de ação alternativo. Na realidade, os autores mostraram que a NTZ pode também atuar como um desacoplador que prejudica o potencial de membrana e a homeostase de pH intraorganismo. (de Carvalho, Darby et al. , 2011) .PFOR, thus suggesting an alternative mechanism of action. In reality, the authors have shown that NTZ can also act as a decoupler that impairs membrane potential and intraorganism pH homeostasis. (de Carvalho, Darby et al., 2011).
[0003] Os efeitos f armacológicos de NTZ não são restritos a suas atividades antiparasitárias ou antibacterianas e, nos últimos anos, diversos estudos revelaram que a NTZ também pode conferir atividade antiviral (Di Santo e Ehrisman, 2014; Rossignol, 2014) . A NTZ interfere na replicação viral por diversas vias incluindo um bloqueio na maturação de proteínas hemaglutinina (influenza) ou VP7 (rotavirus), ou na ativação da proteína PKR envolvida na resposta imune inata (para uma análise, consultar (Rossignol, 2014)) . NTZ também foi demonstrada como tendo propriedades anticâncer amplas pela interferência em vias de sinalização pró-óbito e metabólicas cruciais (Di Santo e Ehrisman, 2014) .[0003] The pharmacological effects of NTZ are not restricted to its antiparasitic or antibacterial activities and, in recent years, several studies have revealed that NTZ can also confer antiviral activity (Di Santo and Ehrisman, 2014; Rossignol, 2014). NTZ interferes with viral replication by several routes including a block in the maturation of hemagglutinin (influenza) or VP7 (rotavirus) proteins, or in the activation of the PKR protein involved in the innate immune response (for an analysis, see (Rossignol, 2014)). NTZ has also been shown to have broad anticancer properties by interfering with crucial pro-death and metabolic signaling pathways (Di Santo and Ehrisman, 2014).
[0004] Os PPARs (α, β/δ (no presente documento após δ), e y) , pertencem à família de receptor nuclear ativado por hormônio. Os PPARs, ou Receptores Ativados Proliferadores de Peroxissomos, são receptores nucleares da superfamília de fatores de transcrição ativados pelos seguintes aglutinantes: esteroides/hormônios da tiroide/retinoides. Até o presente momento, três isótipos de PPAR foram identificados em camundongos e seres humanos: PPARa, PPARõ e PPARy. Embora a expressão de ΡΡΑΡβ/δ em seres humanos pareça ser ubíqua, PPARa e γ exibem uma distribuição de tecido diferencial (Braissant O e Wahli W, 1998). PPARa é expresso em células com alta atividade catabólica de ácido[0004] PPARs (α, β / δ (in this document after δ), and y), belong to the hormone-activated nuclear receptor family. PPARs, or Peroxisome Proliferating Activated Receptors, are nuclear receptors of the transcription factor superfamily activated by the following binders: steroids / thyroid hormones / retinoids. To date, three PPAR isotypes have been identified in mice and humans: PPARa, PPARõ and PPARy. Although the expression of ΡΡΑΡβ / δ in humans appears to be ubiquitous, PPARa and γ exhibit a differential tissue distribution (Braissant O and Wahli W, 1998). PPARa is expressed in cells with high catabolic acid activity
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3/70 graxo e em células com alta atividade peroxissomal (hepatócitos, cardiomiócitos, túbulos proximais renais, mucosa intestinal). PPARp/õ é expresso de modo ubíquo e em abundância na maioria dos tecidos. Ao que se refere à expressão de PPARy, a mesma é limitada principalmente ao tecido adiposo, certas células do sistema imunológico e retina e está presente apenas em quantidades-traço em outros órgãos (Braissant O e Wahli W, 1998) .3/70 fatty and in cells with high peroxisomal activity (hepatocytes, cardiomyocytes, renal proximal tubules, intestinal mucosa). PPARp / õ is expressed ubiquitously and in abundance in most tissues. As regards the expression of PPARy, it is mainly limited to adipose tissue, certain cells of the immune system and retina and is present only in trace amounts in other organs (Braissant O and Wahli W, 1998).
[0005] Tomando o exemplo de PPARa, sua ação é mediada por uma classe de compostos como os fibratos que têm um efeito de redução de lipídio. Os aglutinantes naturais também foram identificados como, por exemplo, ácidos graxos, eicosanoides (leucotrieno B4) e ácido 8(S)— hidroxieicosatetraenoico (Kliewer SA et al. , 1997) . Os[0005] Taking the example of PPARa, its action is mediated by a class of compounds such as fibrates that have a lipid-lowering effect. Natural binders have also been identified, for example, fatty acids, eicosanoids (leukotriene B4) and 8 (S) - hydroxyieicosatetraenoic acid (Kliewer SA et al., 1997). The
PPARs foram associados principalmente ao metabolismo de lipídio e glicose. Os ativadores de PPAR, como fibratos, possibilitam uma regulação de colesterol de plasma e concentrações de triglicerídeo por meio de ativação de PPARa (Hourton D et al., 2001) . A terapia de fibrato leva a um aumento na oxidação de ácido graxo no fígado. Os fibratos também diminuem a síntese de triglicerídeos (Staels B e Auwerx J, 1998). Os ativadores de PPARa também são capazes de corrigir o nível de hiperglicemia e insulina. Os fibratos também reduzem a massa de tecido adiposo através de um mecanismo que é independente de consumo de alimento e expressão de gene de leptina (GuerreMillo M et al., 2000) . O interesse terapêutico de agonistas de PPARy foi amplamente investigado no tratamento de diabetes tipo 2 (Spiegelman BM, 1998) . Foi mostrado que agonistas de PPARy restauram a sensibilidade à insulina emPPARs have been associated mainly with lipid and glucose metabolism. PPAR activators, such as fibrates, enable regulation of plasma cholesterol and triglyceride concentrations by activating PPARa (Hourton D et al., 2001). Fibrate therapy leads to an increase in fatty acid oxidation in the liver. Fibrates also decrease triglyceride synthesis (Staels B and Auwerx J, 1998). PPARa activators are also able to correct the level of hyperglycemia and insulin. Fibrates also reduce the mass of adipose tissue through a mechanism that is independent of food consumption and leptin gene expression (GuerreMillo M et al., 2000). The therapeutic interest of PPARy agonists has been widely investigated in the treatment of type 2 diabetes (Spiegelman BM, 1998). PPARy agonists have been shown to restore insulin sensitivity in
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4/70 tecidos-alvo e reduzem a glicose no plasma, niveis de lipidio e insulina, tanto em modelos animais de diabetes tipo 2 quanto em seres humanos (Ram VJ, 2003) . A ativação de PPAR por aglutinantes também desempenha uma função na regulação da expressão de genes que participam de processos como inflamação, angiogênese, proliferação e diferenciação celular, apoptose e as atividades de 1NOS, MMPase e TIMPs. A ativação de PPARaa em queratinócitos resulta em uma cessação de sua proliferação e expressão de genes envolvidos na diferenciação (Komuves LG et al., 2000) . Os PPARs têm propriedades anti-inflamatórias visto que os mesmos interferem negativamente com mecanismos de transcrição que envolvem outros fatores de transcrição como NF-κΒ ou ativadores transcricionais como STAT e AP-1 (Desvergne B e Wahli W, 1999) . As ditas propriedades antiinf lamatórias e antiproliferativas tornam os PPARs (e particularmente PPARa) interessantes alvos terapêuticos para o tratamento de doenças como doenças oclusivas vasculares (aterosclerose, etc.), hipertensão, doenças relacionadas à neovascularização (retinopatia diabética, etc.), doenças inflamatórias (doença inflamatória intestinal, psoriase, etc.) e doenças neoplásticas (carcinogênese, etc.).4/70 target tissues and reduce plasma glucose, lipid and insulin levels, both in animal models of type 2 diabetes and in humans (Ram VJ, 2003). The activation of PPAR by binders also plays a role in regulating the expression of genes that participate in processes such as inflammation, angiogenesis, cell proliferation and differentiation, apoptosis and the activities of 1NOS, MMPase and TIMPs. The activation of PPARaa in keratinocytes results in a cessation of its proliferation and expression of genes involved in differentiation (Komuves LG et al., 2000). PPARs have anti-inflammatory properties since they negatively interfere with transcription mechanisms that involve other transcription factors such as NF-κΒ or transcriptional activators such as STAT and AP-1 (Desvergne B and Wahli W, 1999). Said anti-inflammatory and antiproliferative properties make PPARs (and particularly PPARa) interesting therapeutic targets for the treatment of diseases such as vascular occlusive diseases (atherosclerosis, etc.), hypertension, diseases related to neovascularization (diabetic retinopathy, etc.), inflammatory diseases (inflammatory bowel disease, psoriasis, etc.) and neoplastic diseases (carcinogenesis, etc.).
[0006] A presente invenção descreve combinações inovadoras de análogos de NTZ, e agonistas de PPAR e seu uso em terapia, em particular, no tratamento de doenças inflamatórias, metabólicas, fibróticas e colestáticas.[0006] The present invention describes innovative combinations of NTZ analogs, and PPAR agonists and their use in therapy, in particular, in the treatment of inflammatory, metabolic, fibrotic and cholestatic diseases.
[0007] Os inventores constataram que NTZ, um agente antiprotozoário sintético ou seus derivados ou seus metabólitos em combinação com agonistas de PPAR, mostram[0007] The inventors found that NTZ, a synthetic antiprotozoal agent or its derivatives or its metabolites in combination with PPAR agonists, show
Petição 870190071527, de 26/07/2019, pág. 19/109Petition 870190071527, of 7/26/2019, p. 10/199
5/70 atividades terapêuticas que são úteis em terapia, em particular para o tratamento de doenças imunes inflamatórias, metabólicas, fibróticas ou colestáticas.5/70 therapeutic activities that are useful in therapy, in particular for the treatment of inflammatory, metabolic, fibrotic or cholestatic immune diseases.
[0008][0008]
Portanto, a presente invenção se refere a um produto de combinação que compreende:Therefore, the present invention relates to a combination product which comprises:
um composto selecionado a partir de NTZ e um análogo do mesmo; e (ii) pelo menos um agonista de PPAR.a compound selected from NTZ and an analog thereof; and (ii) at least one PPAR agonist.
[0009][0009]
Em uma modalidade particular composto de componente (1) do produto de combinação é um composto da fórmula (I):In a particular embodiment the component (1) compound of the combination product is a compound of the formula (I):
ou um sal farmacêutico aceitável do mesmo no qual:or an acceptable pharmaceutical salt thereof in which:
RI representa um átomo de hidrogênio (H) , um átomo de deutério (D) , um átomo de halogênio, um grupo (C6 — C14)arila, um grupo heterocíclico, um grupo (C3C14)cicloalquila, um grupo (C1-C6)alquila, um grupo sulfonila, um grupo sulfóxido, um grupo (Cl— C6)alquilcarbonila, um (C1-C6)aquilóxi, um grupo carboxílico, um grupo carboxilato, um grupo nitro (N02), um grupo amino (NH2), um grupo (C1-C6)alquilamino, um grupo amido, um grupo (C1-C6)alquilamido, um grupo (Cl—RI represents a hydrogen atom (H), a deuterium atom (D), a halogen atom, an aryl (C6 - C14) group, a heterocyclic group, a cycloalkyl (C3C14) group, a (C1-C6) group alkyl, a sulfonyl group, a sulfoxide group, a (C1-C6) alkylcarbonyl group, a (C1-C6) alkyloxy, a carboxyl group, a carboxylate group, a nitro group (N02), an amino group (NH2), an (C1-C6) alkylamino group, a starch group, a (C1-C6) alkylamido group, a (Cl—
Petição 870190071527, de 26/07/2019, pág. 20/109Petition 870190071527, of 7/26/2019, p. 10/20
6/706/70
C6)dialquilamido.C6) dialkyl starch.
R2 representa um átomo de hidrogênio, um átomo de deutério, um grupo N02, um grupo (C6-C14)arila, um grupo heterociclico, um átomo de halogênio, um grupo (Cl— C6)alquila, um grupo (C3-C14)cicloalquila, um grupo (C2C6)alquinila, um grupo (C1-C6)aquilóxi, um grupo (Cl— C6)alquiltio, um grupo (C1-C6)alquilcarbonila, um grupo (C1-C6)alquilcarbonilamino, um grupo (C6— C14)arilcarbonilamino, um grupo carboxilico ou carboxilato, um grupo amido, um grupo (C1-C6)alquilamido, um grupo (Cl— C6) dialquilamido, um grupo NH2, um grupo (Cl — C6)alquilamino, ou RI e R2, juntamente com os átomos de carbono ao qual são fixados, formam um grupo cicloalquila, heterociclica ou arila de 5 a 8 membros substituído ou não substituído,R2 represents a hydrogen atom, a deuterium atom, an N02 group, a (C6-C14) aryl group, a heterocyclic group, a halogen atom, an (Cl— C6) alkyl group, a (C3-C14) group cycloalkyl, an (C2C6) alkynyl group, a (C1-C6) alkyloxy group, a (C1-C6) alkylthio group, a (C1-C6) alkylcarbonyl group, a (C1-C6) alkylcarbonylamino group, a (C6— C14) arylcarbonylamino, a carboxylic or carboxylate group, a starch group, a (C1-C6) alkylamido group, a (Cl-C6) dialkylamido group, an NH2 group, a (Cl - C6) alkylamino group, or RI and R2, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 5- to 8-membered cycloalkyl, heterocyclic or aryl group,
R3, R4, R5, R6, e R7, idênticos ou diferentes, representam um átomo de hidrogênio, um átomo de deutério, um átomo de halogênio, um grupo hidroxila, um grupo (Cl— C6)alquilcarbonila, um grupo (C1-C6)alquila, um grupo (Cl— C6)aquilóxi, um grupo (C1-C6)alquiltio, um grupo (Cl— C6)alquilcarbonilóxi, um grupo (C6-C14)arilóxi, um grupo (C6-C14)arila, um grupo heterociclico, um grupo (C3C14)cicloalquila, um grupo N02, um grupo sulfonilaminoalquila, um grupo NH2, um grupo amino(Cl— C6) alquila, um grupo (C1-C6)alquilcarbonilamino, um grupo carboxilico, um grupo carboxilato ou um grupo R9;R3, R4, R5, R6, and R7, identical or different, represent a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a (C1-C6) alkylcarbonyl group, a (C1-C6 ) alkyl, a (C1-C6) alkyloxy group, a (C1-C6) alkylthio group, a (C1-C6) alkylcarbonyloxy group, a (C6-C14) aryloxy group, a (C6-C14) aryl group, a group heterocyclic, a (C3C14) cycloalkyl group, an N02 group, a sulfonylaminoalkyl group, an NH2 group, an amino (C1-C6) alkyl group, a (C1-C6) alkylcarbonylamino group, a carboxyl group, a carboxylate group or a group R9;
R9 representa um grupo 0-R8 ou um aminoácido selecionado a partir do grupo que consiste em alanina, arginina, asparagina, ácido aspártico, cisteína, glutamina, ácido glutâmico, glicina, histidina, isoleucina, leucina, lisina,R9 represents a group 0-R8 or an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine,
Petição 870190071527, de 26/07/2019, pág. 21/109Petition 870190071527, of 7/26/2019, p. 10/21
7/70 metionina, fenilalanina, prolina, serina, treonina, triptofano, tirosina, valina, ou uma fração da fórmula (A): O R7/70 methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a fraction of formula (A): O R
R' (A) em que R' representa um grupo (C1-C6)alquila, um grupo (C2C6)alquenila, um grupo (C2-C6)alquinila, um grupo (C3C14)cicloalquila, grupo (C3-C14)cicloalquilalquila, urn grupo (C3-C14)cicloalquil(C2-C6)alquenila, um grupo (C3C14)cicloalquenila, um grupo (C3-C14)cicloalquenil(Cl— C6)alquila, um grupo (C3-C14)cicloalquenil(C2-C6)alquenila, um grupo (C3-C14)cicloalquenil(C2-C6)alquinila; R e R' , independentemente, representam átomo de hidrogênio, um grupo (C1-C6)alquila ou um grupo de proteção de nitrogênio.R '(A) where R' represents a (C1-C6) alkyl group, a (C2C6) alkenyl group, a (C2-C6) alkynyl group, a (C3C14) cycloalkyl group, (C3-C14) cycloalkylalkyl group, a (C3-C14) cycloalkyl (C2-C6) alkenyl group, a (C3C14) cycloalkenyl group, a (C3-C14) cycloalkenyl (C1-C6) alkyl group, a (C3-C14) cycloalkenyl (C2-C6) group alkenyl, a (C3-C14) cycloalkenyl (C2-C6) alkynyl group; R and R ', independently, represent hydrogen atom, a (C1-C6) alkyl group or a nitrogen protecting group.
oThe
R8cR 8 c
R8 representa um átomo de hidrogênio, um átomo de deutério, um grupo glicuronidila, ou um grupo em que, R8a, R8b e R8c, idênticos ou diferentes, representam um átomo de hidrogênio ou um átomo de deutério.R8 represents a hydrogen atom, a deuterium atom, a glucuronidyl group, or a group in which, identical or different, R8a, R8b and R8c, represent a hydrogen atom or a deuterium atom.
[0010] Em uma modalidade particular adicional, o composto de componente (i) do produto de combinação é um composto da fórmula (I):[0010] In a particular additional embodiment, the component compound (i) of the combination product is a compound of the formula (I):
Petição 870190071527, de 26/07/2019, pág. 22/109Petition 870190071527, of 7/26/2019, p. 10/22
8/708/70
ou um sal farmacêutico aceitável do mesmo, no qual:or an acceptable pharmaceutical salt thereof, in which:
RI representa um átomo de hidrogênio (H) , um átomo de deutério (D) , um átomo de halogênio, um grupo (C6 — C14)arila, um grupo heterocíclico, um grupo (C3C14)cicloalquila, um grupo (C1-C6)alquila, um grupo sulfonila, um grupo sulfóxido, um grupo (Cl— C6)alquilcarbonila, um (C1-C6)aquilóxi, um grupo carboxílico, um grupo carboxilato, um grupo NO2, um grupo NH2, um grupo (C1-C6)alquilamino, um grupo amido, um grupo (C1-C6)alquilamido, um grupo (C1-C6)dialquilamido.RI represents a hydrogen atom (H), a deuterium atom (D), a halogen atom, an aryl (C6 - C14) group, a heterocyclic group, a cycloalkyl (C3C14) group, a (C1-C6) group alkyl, a sulfonyl group, a sulfoxide group, a (C1-C6) alkylcarbonyl group, an (C1-C6) alkyloxy, a carboxylic group, a carboxylate group, a NO2 group, an NH2 group, a (C1-C6) group alkylamino, a starch group, a (C1-C6) alkyl starch group, a (C1-C6) dialkyl starch group.
R2 representa um átomo de hidrogênio, um átomo de deutério, um grupo N02, um grupo (C6-C14)arila, um grupo heterocíclico, um átomo de halogênio, um grupo (Cl— C6)alquila, um grupo (C3-C14)cicloalquila, um grupo (C2C6)alquinila, um grupo (C1-C6)aquilóxi, um grupo (Cl— C6)alquiltio, um grupo (C1-C6)alquilcarbonila, um grupo (C1-C6)alquilcarbonilamino, um grupo (C6— C14)arilcarbonilamino, um grupo carboxílico ou carboxilato, um grupo amido, um grupo (C1-C6)alquilamido, um grupo (Cl— C6)dialquilamido, um grupo NH2, um grupo (Cl — C6)alquilamino,R2 represents a hydrogen atom, a deuterium atom, an N02 group, a (C6-C14) aryl group, a heterocyclic group, a halogen atom, an (Cl— C6) alkyl group, a (C3-C14) group cycloalkyl, an (C2C6) alkynyl group, a (C1-C6) alkyloxy group, a (C1-C6) alkylthio group, a (C1-C6) alkylcarbonyl group, a (C1-C6) alkylcarbonylamino group, a (C6— C14) arylcarbonylamino, a carboxylic or carboxylate group, a starch group, a (C1-C6) alkylamido group, a (Cl-C6) dialkylamido group, an NH2 group, an (Cl - C6) alkylamino group,
Petição 870190071527, de 26/07/2019, pág. 23/109Petition 870190071527, of 7/26/2019, p. 10/23
9/70 ou RI e R2, juntamente com os átomos de carbono ao qual são fixados, formam um grupo cicloalquila, heterociclica ou arila de 5 a 8 membros substituído ou não substituído,9/70 or RI and R2, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 5- to 8-membered cycloalkyl, heterocyclic or aryl group,
R3 representa um átomo de hidrogênio, um átomo de deutério, um átomo de halogênio, um grupo 0-R8, um grupo (Cl— C6)alquilcarbonila, um grupo (C1-C6)alquila, um grupo (Cl— C6)aquilóxi, um grupo (C1-C6)alquiltio, um grupo (Cl— C6)alquilcarbonilóxi, um grupo (C6-C14)arilóxi, um grupo (C6-C14)arila, um grupo heterocíclico, um grupo (C3C14)cicloalquila, um N02, um grupo sulfonilaminoalquila, um grupo NH2, um grupo amino (C1-C6) alquila, um grupo (Cl — C6)alquilcarbonilamino, um grupo carboxílico, um grupo carboxilato, um aminoácido selecionado a partir do grupo que consiste em alanina, arginina, asparagina, ácido aspártico, cisteína, glutamina, ácido glutâmico, glicina, histidina, isoleucina, leucina, lisina, metionina, fenilalanina, prolina, serina, treonina, triptofano, tirosina, valina, ou uma fração da fórmula (A) :R3 represents a hydrogen atom, a deuterium atom, a halogen atom, a 0-R8 group, a (Cl— C6) alkylcarbonyl group, a (C1-C6) alkyl group, an (Cl— C6) alkyloxy group, a (C1-C6) alkylthio group, a (C1-C6) alkylcarbonyloxy group, a (C6-C14) aryloxy group, a (C6-C14) aryl group, a heterocyclic group, a (C3C14) cycloalkyl group, an N02, a sulfonylaminoalkyl group, an NH2 group, an amino (C1-C6) alkyl group, a (Cl - C6) alkylcarbonylamino group, a carboxylic group, a carboxylate group, an amino acid selected from the group consisting of alanine, arginine, asparagine , aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a fraction of formula (A):
O RThe R
R' (A) em que R' representa um grupo (C1-C6) alquila, um grupo (C2C6)alquenila, um grupo (C2-C6)alquinila, um grupo (C3C14)cicloalquila, grupo (C3-C14)cicloalquilalquila, um grupo (C3-C14)cicloalquil(C2-C6)alquenila, um grupo (C3C14)cicloalquenila, um grupo (C3-C14)cicloalquenil(Cl— C6)alquila, um grupo (C3-C14)cicloalquenil(C2-C6)alquenila,R '(A) where R' represents a (C1-C6) alkyl group, a (C2C6) alkenyl group, a (C2-C6) alkynyl group, a (C3C14) cycloalkyl group, (C3-C14) cycloalkylalkyl group, a (C3-C14) cycloalkyl (C2-C6) alkenyl group, a (C3C14) cycloalkenyl group, a (C3-C14) cycloalkenyl (Cl— C6) alkyl group, a (C3-C14) cycloalkenyl (C2-C6) group alkenyl,
Petição 870190071527, de 26/07/2019, pág. 24/109Petition 870190071527, of 7/26/2019, p. 10/24
10/70 um grupo (C3-C14)cicloalquenil(C2-C6)alquinila; R e R' , independentemente, representam átomo de hidrogênio, um grupo (C1-C6)alquila ou um grupo de proteção de nitrogênio. R8 representa um átomo de hidrogênio, um átomo de deutério, a10/70 a (C3-C14) cycloalkenyl (C2-C6) alkynyl group; R and R ', independently, represent hydrogen atom, a (C1-C6) alkyl group or a nitrogen protecting group. R8 represents a hydrogen atom, a deuterium atom, the
ou um grupo oor a group o
em que,on what,
R8aR8a
R8b e R8c, idênticos ou diferentes, representam um átomo de hidrogênio ou um átomo de deutério.R8b and R8c, identical or different, represent a hydrogen atom or a deuterium atom.
R4, R5, R6, e R7, idênticos ou diferentes, representam um átomo de hidrogênio, um átomo de deutério, um átomo de halogênio, um grupo hidroxila, um grupo (Cl— C6)alquilcarbonila, um grupo (C1-C6)alquila, um grupo (Cl— C6)aquilóxi, um grupo (C1-C6)alquiltio, um grupo (Cl— C6)alquilcarbonilóxi, um grupo (C6-C14)arilóxi, um grupo (C6-C14)arila, um grupo heterociclico, um grupo (C3C14)cicloalquila, um N02, um grupo sulfonilamino(Cl— C6)alquila, um grupo NH2, um grupo amino(C1-C6)alquila, um grupo (C1-C6)alquilcarbonilamino, um grupo carboxilico, um grupo carboxilato, um aminoácido selecionado a partir do grupo que consiste em alanina, arginina, asparagina, ácido aspártico, cisteina, glutamina, ácido glutâmico, glicina, histidina, isoleucina, leucina, lisina, metionina, fenilalanina, prolina, serina, treonina, triptofano, tirosina, valina, ou uma fração da fórmula (A) :R4, R5, R6, and R7, identical or different, represent a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a (C1-C6) alkylcarbonyl group, a (C1-C6) alkyl group , a (C1-C6) alkyloxy group, a (C1-C6) alkylthio group, a (C1-C6) alkylcarbonyloxy group, a (C6-C14) aryloxy group, a (C6-C14) aryl group, a heterocyclic group, a (C3C14) cycloalkyl group, an N02, a sulfonylamino (C1-C6) alkyl group, an NH2 group, an amino (C1-C6) alkyl group, a (C1-C6) alkylcarbonylamino group, a carboxylic group, a carboxylate group , an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine , valine, or a fraction of formula (A):
oThe
R’ (A)R ’(A)
Petição 870190071527, de 26/07/2019, pág. 25/109Petition 870190071527, of 7/26/2019, p. 10/25
11/70 em que R' representa um grupo (C1-C6)alquila, um grupo (C2C6)alquenila, um grupo (C2-C6)alquinila, um grupo (C3C14)cicloalquila, grupo (C3-C14)cicloalquil(C1-C6)alquila, um grupo (C3-C14)cicloalquil(C1-C6)alquenila, um grupo (C3C14)cicloalquenila, um grupo (C3-C14)cicloalquenil(Cl— C6)alquila, um grupo (C3-C14)cicloalquenil(C2-C6)alquenila, um grupo (C3-C14)cicloalquenil(C2-C6)alquinila; R e R' , independentemente, representam um átomo de hidrogênio, um grupo (C1-C6)alquila ou um grupo de proteção de nitrogênio; ou um sal farmaceuticamente aceitável do mesmo.11/70 where R 'represents a (C1-C6) alkyl group, a (C2C6) alkenyl group, a (C2-C6) alkynyl group, a (C3C14) cycloalkyl group, (C3-C14) cycloalkyl (C1-) group C6) alkyl, a (C3-C14) cycloalkyl (C1-C6) alkenyl group, a (C3C14) cycloalkenyl group, a (C3-C14) cycloalkenyl (Cl— C6) alkyl group, a (C3-C14) cycloalkenyl group ( C2-C6) alkenyl, a (C3-C14) cycloalkenyl (C2-C6) alkynyl group; R and R ', independently, represent a hydrogen atom, a (C1-C6) alkyl group or a nitrogen protecting group; or a pharmaceutically acceptable salt thereof.
[0011] Em uma modalidade particular, no composto da fórmula (I) da presente invenção: um grupo (C1-C6)alquila pode ser um grupo (C1-C6)alquila substituído ou não substituído, em particular, um grupo (C1-C4)alquila substituído ou não substituído;[0011] In a particular embodiment, in the compound of the formula (I) of the present invention: a (C1-C6) alkyl group can be a substituted or unsubstituted (C1-C6) alkyl group, in particular, a (C1-) group C4) substituted or unsubstituted alkyl;
um grupo (C2-C6)alquinila pode ser um grupo (C2C6)alquinila substituído ou não substituído; um grupo (C3C14)cicloalquila pode ser um grupo (C3-C14)cicloalquila substituído ou não substituído, um grupo (C1-C6)aquilóxi pode ser substituído ou não substituído, como um grupo (Cl— C4)aquilóxi substituído ou não substituído;an (C2-C6) alkynyl group can be a substituted or unsubstituted (C2C6) alkynyl group; a (C3C14) cycloalkyl group can be a substituted or unsubstituted (C3-C14) cycloalkyl group, an (C1-C6) alkyloxy group can be substituted or unsubstituted, such as a substituted or unsubstituted (C1-C4) alkyloxy group;
um grupo (C1-C6)alquiltio pode ser substituído ou não substituído, como um grupo (C1-C4)alquiltio substituído ou não substituído;an (C1-C6) alkylthio group can be substituted or unsubstituted, such as a substituted or unsubstituted (C1-C4) alkylthio group;
um grupo (C1-C6)alquilamino pode ser um grupo (Cl — C4)alquilamino;a (C1-C6) alkylamino group can be a (Cl - C4) alkylamino group;
um grupo (C1-C6)dialquilamino pode ser um grupo (Cl— C4)dialquilamino ;a (C1-C6) dialkylamino group can be a (C1-C4) dialkylamino group;
um grupo (C6-C14)arila pode ser um grupo (C6-C14)arila substituído ou não substituído;an (C6-C14) aryl group can be a substituted or unsubstituted (C6-C14) aryl group;
Petição 870190071527, de 26/07/2019, pág. 26/109Petition 870190071527, of 7/26/2019, p. 10/26
12/70 um grupo heterocíclico pode ser um grupo heterocicloalquila ou heteroarila substituído ou não substituído.12/70 a heterocyclic group can be a substituted or unsubstituted heterocycloalkyl or heteroaryl group.
[0012] Em uma modalidade particular, o composto de componente (i) do produto de combinação é um composto da fórmula (II) em que R9 representa um átomo de hidrogênio, um átomo de deutério, um grupo 0-R8 (R8 é definido acima), ou um aminoácido selecionado a partir do grupo que consiste em alanina, arginina, asparagina, ácido aspártico, cisteína, glutamina, ácido glutâmico, glicina, histidina, isoleucina, leucina, lisina, metionina, fenilalanina, prolina, serina, treonina, triptofano, tirosina, valina, ou uma fração da fórmula (A):[0012] In a particular embodiment, the compound component (i) of the combination product is a compound of the formula (II) in which R9 represents a hydrogen atom, a deuterium atom, a group 0-R8 (R8 is defined above), or an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a fraction of formula (A):
oThe
R (A):R (A):
em que R' representa um grupo (C1-C6) alquila, um grupo (C2C6)alquenila, um grupo (C2-C6)alquinila, um grupo (C3C14)cicloalquila, grupo (C3-C14)cicloalquil(C1-C6)alquila, um grupo (C3-C14)cicloalquil(C1-C6)alquenila, um grupo (C3C14)cicloalquenila, um grupo (C3-C14)cicloalquenil(Cl— C6)alquila, um grupo (C3-C14)cicloalquenil(C2-C6)alquenila, um grupo (C3-C14)cicloalquenil(C2-C6)alquinila; R e R' ,where R 'represents a (C1-C6) alkyl group, a (C2C6) alkenyl group, a (C2-C6) alkynyl group, a (C3C14) cycloalkyl group, (C3-C14) cycloalkyl (C1-C6) alkyl group , a (C3-C14) cycloalkyl (C1-C6) alkenyl group, a (C3C14) cycloalkenyl group, a (C3-C14) cycloalkenyl (C1-C6) alkyl group, a (C3-C14) cycloalkenyl (C2-C6) group ) alkenyl, a (C3-C14) cycloalkenyl (C2-C6) alkynyl group; R and R ',
Petição 870190071527, de 26/07/2019, pág. 27/109Petition 870190071527, of 7/26/2019, p. 10/279
13/70 independentemente, representam um átomo de hidrogênio, um grupo (C1-C6)alquila, ou um grupo de proteção de nitrogênio ou um sal farmaceuticamente aceitável do mesmo.13/70 independently, they represent a hydrogen atom, a (C1-C6) alkyl group, or a nitrogen protecting group or a pharmaceutically acceptable salt thereof.
[0013] Em uma modalidade particular, o componente (i) do produto de combinação da invenção é selecionado a partir[0013] In a particular embodiment, component (i) of the combination product of the invention is selected from
- NTZ:- NTZ:
- tizoxanida:- tizoxanide:
- tizoxanida glucuronídeo (TZG):- glucuronide tizoxanide (TZG):
[0014] Em uma outra modalidade, o componente (i) do produto de combinação é um composto da fórmula (I) ou (II) em que R8 representa um átomo de hidrogênio, um átomo de[0014] In another embodiment, the component (i) of the combination product is a compound of the formula (I) or (II) in which R8 represents a hydrogen atom, an atom of
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14/70 deutério ou um grupo em que, R8a, R8b e R8c idênticos ou diferentes, representam um átomo de hidrogênio ou um átomo de deutério; e/ou em que Rl, R3, R4, R5, e R6, idênticos ou diferentes, representam um átomo de hidrogênio ou um átomo de deutério com a condição de que Rl, R2, R2a, R2b, R2c, R3, R4, R5, e R6 não sejam simultaneamente um átomo de hidrogênio.14/70 deuterium or a group in which, R8a, R8b and R8c identical or different, represent a hydrogen atom or a deuterium atom; and / or where R1, R3, R4, R5, and R6, identical or different, represent a hydrogen atom or a deuterium atom with the proviso that R1, R2, R2a, R2b, R2c, R3, R4, R5 , and R6 are not simultaneously a hydrogen atom.
[0015] Em uma modalidade particular, o componente (i) é (d3) etanoato de [(5-nitro-l,3-tiazol-2il)carbamoil]fenila, (d2) etanoato de 2-[(5-nitro-l, 3tiazol-2-il)carbamoil]fenila; ou (dl) etanoato de 2—[(5— nitro-1,3-tiazol-2-il)carbamoil]fenila.[0015] In a particular embodiment, component (i) is [(5-nitro-1,3-thiazol-2yl) carbamoyl] phenyl (d3) etanoate 2 - [(5-nitro- 1,3thiazol-2-yl) carbamoyl] phenyl; or 2 - [(5— nitro-1,3-thiazol-2-yl) carbamoyl] phenyl (dl) etanoate.
[0016] Em uma outra modalidade particular, o componente (i) é (cloridrato de 2-amino-3,3-dimetilbutanoato de (S)—2— (5-nitrotiazol-2-ilcarbamoil)fenila) (RM5061) da fórmula:[0016] In another particular embodiment, component (i) is (S) —2— (5-nitrothiazol-2-ylcarbamoyl) phenyl 2-amino-3,3-dimethylbutanoate (RM5061) :
oThe
NO.AT THE.
[0017] Em uma outra modalidade particular, o componente (i) é (cloridrato de 2-amino-3-metilpentanoato de (2S,3S)2-(5-nitrotiazol-2-ilcarbamoil)fenila) (RM5066) da fórmula:[0017] In another particular embodiment, component (i) is (2S, 3S) 2- (5-nitrothiazol-2-ylcarbamoyl) phenyl 2-amino-3-methylpentanoate hydrochloride (RM5066) of the formula:
Petição 870190071527, de 26/07/2019, pág. 29/109Petition 870190071527, of 7/26/2019, p. 10/29
15/7015/70
[0018] Em uma modalidade particular adicional, o agonista de PPAR é um agonista alfa de PPAR, um agonista gama de PPAR, um agonista delta de PPAR, um agonista duplo alfa/gama de PPAR, um agonista duplo alfa/delta de PPAR, um agonista duplo gama/delta de PPAR ou panagonista alfa/gama/delta de PPAR.[0018] In an additional particular embodiment, the PPAR agonist is an PPAR alpha agonist, a PPAR gamma agonist, a PPAR delta agonist, a PPAR alpha / gamma double agonist, a PPAR alpha / delta agonist, a PPAR gamma / delta double agonist or PPAR alpha / gamma / delta agonist.
[0019] De acordo com a invenção, o agonista (ou agonistas) de PPAR e o componente (i) compreendidos na combinação da invenção podem ser selecionados de modo que a combinação do dito agonista (ou agonistas) de PPAR e componente (i) da combinação da invenção forneça uma ação sinérgica contra doenças inflamatórias, metabólicas, fibróticas e colestáticas. Tal sinergia pode ser determinada de acordo com métodos bem conhecidos na[0019] According to the invention, the PPAR agonist (or agonists) and component (i) comprised in the combination of the invention can be selected so that the combination of said PPAR agonist (or agonists) and component (i) the combination of the invention provides a synergistic action against inflammatory, metabolic, fibrotic and cholestatic diseases. Such synergy can be determined according to methods well known in the
estar (EOB) descrito nos exemplos.be (EOB) described in the examples.
do produto de combinação é:combination product is:
- pelo menos um agonista alfa de PPAR e pelo menos um agonista delta de PPAR;- at least one PPAR alpha agonist and at least one PPAR delta agonist;
- pelo menos um agonista duplo alfa/gama de PPAR;- at least one PPAR alpha / gamma double agonist;
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16/7016/70
- pelo menos um agonista alfa de PPAR e pelo menos um agonista gama de PPAR;- at least one PPAR alpha agonist and at least one PPAR gamma agonist;
- pelo menos um agonista duplo gama/delta de PPAR;- at least one PPAR gamma / delta double agonist;
- pelo menos um agonista gama de PPAR e pelo menos um agonista delta de PPAR;- at least one PPAR gamma agonist and at least one PPAR delta agonist;
- pelo menos um panagonista alfa/gama/delta de PPAR; e- at least one PPAR alpha / gamma / delta panagonist; and
- pelo menos um agonista alfa de PPAR, pelo menos um agonista gama de PPAR e pelo menos um agonista delta de PPAR.- at least one PPAR alpha agonist, at least one PPAR gamma agonist and at least one PPAR delta agonist.
[0021] De acordo com a presente invenção, o termo agonistas de PPAR (ou PPARs) se refere aos agonistas de Receptor Ativado Proliferador de Peroxissomo, que são uma classe de fármacos que desempenham um papel central em homeostase de lipideo e glicose. PPARa influencia principalmente no metabolismo de ácido graxo e sua ativação diminui os níveis de lipídio, enquanto PPARy está em sua maior parte envolvido na regulação da adipogênese, equilíbrio de energia e biossíntese de lipídio. PPARõ participa em oxidação de ácido graxo, em sua maior parte, em músculos cardíacos e esqueletais, mas também regula os níveis de colesterol e glicose sanguínea.[0021] According to the present invention, the term PPAR agonists (or PPARs) refers to Peroxisome Proliferating Activated Receptor agonists, which are a class of drugs that play a central role in lipid and glucose homeostasis. PPARa mainly influences fatty acid metabolism and its activation decreases lipid levels, while PPARy is mostly involved in the regulation of adipogenesis, energy balance and lipid biosynthesis. PPARõ participates in fatty acid oxidation, for the most part, in heart and skeletal muscles, but it also regulates cholesterol and blood glucose levels.
[0022] De acordo com a invenção, o termo agonista alfa de PPAR, como usado no presente documento, inclui, mas não é limitado a, fenofibrato, ciprofibrato, pemafibrato, genfibrozila, clofibrato, binifibrato, clinofibrato, ácido clofíbrico, nicofibrato, pirifibrato, plafibride, ronifibrato, teofibrato, tocofibrato e SR10171.[0022] According to the invention, the term PPAR alpha agonist, as used herein, includes, but is not limited to, fenofibrate, ciprofibrate, pemafibrate, genfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pyrifibrate , plafibride, ronifibrate, theofibrate, tocofibrate and SR10171.
[0023] De acordo com a invenção, o termo agonista gama de PPAR, como usado no presente documento, inclui, mas não é limitado a, Rosiglitazona, Pioglitazona, pioglitazona[0023] According to the invention, the term gamma agonist of PPAR, as used herein, includes, but is not limited to, Rosiglitazone, Pioglitazone, pioglitazone
Petição 870190071527, de 26/07/2019, pág. 31/109Petition 870190071527, of 7/26/2019, p. 10/319
17/70 deuterada, Efatutazona, ATx08-001, OMS-405, CHS-131, THR0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001 e17/70 deuterated, Efatutazone, ATx08-001, WHO-405, CHS-131, THR0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001 and
ALL-4 .ALL-4.
[0024] De acordo com a invenção, o termo agonista delta de PPAR, como usado no presente documento, inclui, mas não é limitado a, GW501516 (Endurabol ou (ácido {4-[ ({4-metil2- [4- (trifluorometil)fenil]-1,3-tiazol-5il}metil) suitanil]-2-metilfenoxi}acético) ), MBX802 5 (Seladelpar ou ácido {2-metil-4-[5-metil-2-(4trifluorometil-fenil)-2H-[1,2,3]triazol-4-ilmetilsulfanil]fenoxi}-acético), GW0742 (ácido [4-[ [ [2-[3-fluoro-4(trifluorometil)fenil]-4-metil-5-tiazolil]metil]tio]-2metil fenoxi]acético), L165041, HPP-593 e NCP-1046.[0024] According to the invention, the term PPAR delta agonist, as used herein, includes, but is not limited to, GW501516 (Endurabol or ({4- [({4-methyl2- [4- ( trifluoromethyl) phenyl] -1,3-thiazol-5yl} methyl) suitanyl] -2-methylphenoxy} acetic)), MBX802 5 (Seladelpar or {2-methyl-4- [5-methyl-2- (4trifluoromethyl-phenyl) ) -2H- [1,2,3] triazol-4-ylmethylsulfanyl] phenoxy} -acetic), GW0742 ([4- [[[2- [3-fluoro-4 (trifluoromethyl) phenyl] -4-methyl- 5-thiazolyl] methyl] thio] -2methyl phenoxy] acetic), L165041, HPP-593 and NCP-1046.
[0025] De acordo com a invenção, o termo agonista alfa/gama de PPAR (também chamado de glitazares) usado no presente documento inclui, mas não é limitado a, Saroglitazar, Aleglitazar, Muraglitazar, Tesaglitazar e DSP-8658.[0025] According to the invention, the term PPAR alpha / gamma agonist (also called glitazars) used in this document includes, but is not limited to, Saroglitazar, Aleglitazar, Muraglitazar, Tesaglitazar and DSP-8658.
[0026] De acordo com a invenção, o termo agonista alfa/delta de PPAR usado no presente documento inclui, mas não é limitado a, Elafibranor (GFT505) ou T913659.[0026] According to the invention, the term PPAR alpha / delta agonist used in this document includes, but is not limited to, Elafibranor (GFT505) or T913659.
[0027] De acordo com a invenção, o termo agonista gama/delta de PPAR usado no presente documento inclui, mas não é limitado a, um ácido linoleico conjugado (CLA), T3D959.[0027] According to the invention, the term PPAR gamma / delta agonist used in this document includes, but is not limited to, a conjugated linoleic acid (CLA), T3D959.
[0028] De acordo com a invenção, o termo agonista alfa/gama/delta de PPAR usado no presente documento inclui, mas não é limitado a, IVA337 (Lanifibranor) , TTA (ácido tetradeciltioacético) , Bavaquinina, GW4148, GW9135, Bezafibrato, Lobeglitazona e CS038. Em uma modalidade[0028] According to the invention, the term PPAR alpha / gamma / delta agonist used in this document includes, but is not limited to, IVA337 (Lanifibranor), TTA (tetradecylthioacetic acid), Bavaquinina, GW4148, GW9135, Bezafibrato, Lobeglitazone and CS038. In a modality
Petição 870190071527, de 26/07/2019, pág. 32/109Petition 870190071527, of 7/26/2019, p. 10/32
18/70 adicional, o agonista alfa/gama/delta de PPAR é ácido 2—(4— (5,6-metilenodioxibenzo[d]tiazol-2-il)-2-metilfenoxi)-2metilpropanoico (MHY2013).In addition, the PPAR alpha / gamma / delta agonist is 2— (4— (5,6-methylenedioxybenzo [d] thiazol-2-yl) -2-methylphenoxy) -2methylpropanoic acid (MHY2013).
[0029] 0 agonista de PPAR pode estar na forma de um sal, hidrato, solvato, polimorfo ou um cocristal. 0 agonista de[0029] The PPAR agonist can be in the form of a salt, hydrate, solvate, polymorph or a cocrystal. The agonist of
PPAR também pode estar na forma de um hidrato, solvato, polimorfo ou um cocristal de um sal.PPAR can also be in the form of a hydrate, solvate, polymorph or a salt cocrystal.
[0030] Em uma modalidade mais particular, o agonista de[0030] In a more particular modality, the agonist of
PPAR é um composto da fórmula (III), ou um sal farmaceuticamente aceitável do mesmo:PPAR is a compound of the formula (III), or a pharmaceutically acceptable salt thereof:
em que:on what:
Y1 representa um halogênio, um Ra ou grupo Ga-Ra;Y1 represents a halogen, a Ra or Ga-Ra group;
A representa um CH=CH ou um grupo CH2-CH2;A represents a CH = CH or a CH2-CH2 group;
Y2 representa um grupo Gb-Rb;Y2 represents a Gb-Rb group;
Ga e Gb, idênticos ou diferentes, representam um átomo de oxigênio ou enxofre;Ga and Gb, identical or different, represent an oxygen or sulfur atom;
Ra representa um átomo de hidrogênio, um grupo (Cl— C6)alquila, um grupo (C6-C14)arila ou um grupo (Cl— C6)alquila não substituído que é substituído por um ou mais átomos de halogênio, um grupo (C1-C6)alcóxi ou (Cl— C6)alquiltio, grupos (C3-C14)cicloalquila, grupos (C3C14)cicloalquiltio ou grupos heterocíclicos;Ra represents a hydrogen atom, a (Cl— C6) alkyl group, an (C6-C14) aryl group or an unsubstituted (Cl— C6) alkyl group that is replaced by one or more halogen atoms, a (C1) group -C6) alkoxy or (C1-C6) alkylthio, (C3-C14) cycloalkyl groups, (C3C14) cycloalkylthio groups or heterocyclic groups;
Rb representa um grupo (C1-C6)alquila substituído por pelo menos um grupo -COORc, em que Rc representa a átomo deRb represents a (C1-C6) alkyl group substituted by at least one -COORc group, where Rc represents the atom of
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19/70 hidrogênio, ou um grupo (C1-C6)alquila que é substituído ou19/70 hydrogen, or a (C1-C6) alkyl group that is substituted or
heterocíclicos.heterocyclic.
[0031] Em uma modalidade particular do composto da fórmula (III):[0031] In a particular embodiment of the compound of formula (III):
Y1 representa um halogênio, um Ra ou um grupo Ga-Ra;Y1 represents a halogen, an Ra or a Ga-Ra group;
A representa um grupo CH=CH;A represents a CH = CH group;
Y2 representa um grupo Gb-Rb;Y2 represents a Gb-Rb group;
Ga e Gb, idênticos ou diferentes, representam um átomo de oxigênio ou enxofre;Ga and Gb, identical or different, represent an oxygen or sulfur atom;
Ra representa um grupo (C1-C6)alquila ou (C3C14)cicloalquila, em particular, um grupo (C1-C7)alquila ou (C3-C14) cicloalquila substituído ou não por um ou mais átomos de halogênio;Ra represents a (C1-C6) alkyl or (C3C14) cycloalkyl group, in particular, a (C1-C7) alkyl group or (C3-C14) cycloalkyl substituted or not by one or more halogen atoms;
Rb representa um grupo (C1-C6)alquila substituído por um grupo -COOR3, em que Rc representa um átomo de hidrogênio ou um grupo alquila que tem de um a quatro átomos de carbono; eRb represents a (C1-C6) alkyl group substituted by a -COOR3 group, where Rc represents a hydrogen atom or an alkyl group having one to four carbon atoms; and
Y4 e Y5, independentemente, representam um grupo (Cl— C4)alquila.Y4 and Y5, independently, represent a (C1 -C4) alkyl group.
[0032] Em uma modalidade particular do composto da fórmula (III):[0032] In a particular embodiment of the compound of formula (III):
Y1 representa um grupo Ra ou Ga-Ra;Y1 represents an Ra or Ga-Ra group;
A representa um grupo CH2-CH2;A represents a CH2-CH2 group;
Y2 representa um grupo Gb-Rb;Y2 represents a Gb-Rb group;
Ga representa um átomo de oxigênio ou enxofre e GbGa represents an oxygen or sulfur atom and Gb
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20/70 representa um átomo de oxigênio;20/70 represents an oxygen atom;
Ra representa um grupo (C1-C6)alquila ou (03C7)cicloalquila;Ra represents a (C1-C6) alkyl or (03C7) cycloalkyl group;
Rb representa um grupo (C1-C6)alquila substituído por pelo menos um grupo -COORc, em que Rc representa um átomo de hidrogênio ou grupo (C1-C4)alquila; eRb represents a (C1-C6) alkyl group substituted by at least one -COORc group, where Rc represents a hydrogen atom or (C1-C4) alkyl group; and
Y4 e Y5, independentemente, representam um grupo (Cl— C4)alquila.Y4 and Y5, independently, represent a (C1 -C4) alkyl group.
[0033] Em uma modalidade particular do composto da fórmula (III):[0033] In a particular embodiment of the compound of formula (III):
Y1 representa um átomo de hidrogênio ou um grupo Ra ou GaRa;Y1 represents a hydrogen atom or a Ra or GaRa group;
A representa um grupo CH2-CH2;A represents a CH2-CH2 group;
Y2 representa um grupo Gb-Rb;Y2 represents a Gb-Rb group;
Ga representa um átomo de oxigênio ou enxofre e Gb representa um átomo de oxigênio;Ga represents an oxygen or sulfur atom and Gb represents an oxygen atom;
Ra representa um grupo (C1-C6)alquila ou (C3C14)cicloalquila que é substituído por um ou mais átomos de halogênio;Ra represents a (C1-C6) alkyl or (C3C14) cycloalkyl group that is replaced by one or more halogen atoms;
Rb representa um grupo (C1-C6)alquila substituído ou não por um ou mais átomos de halogênio e substituídos por pelo menos um grupo -COORc, em que Rc representa um átomo de hidrogênio ou um grupo (C1-C4)alquila; eRb represents a (C1-C6) alkyl group whether or not substituted by one or more halogen atoms and replaced by at least one -COORc group, where Rc represents a hydrogen atom or a (C1-C4) alkyl group; and
Y4 e Y5 representam um grupo (C1-C4)alquila.Y4 and Y5 represent a (C1-C4) alkyl group.
[0034] Em uma modalidade particular do composto de fórmula (III), Gb é um oxigênio átomo e Rb é grupo (Cl — C6)alquila substituído por um grupo -COORc, em que Rc representa um átomo de hidrogênio ou um grupo (Cl— 04)alquila não substituído linear ou ramificado.[0034] In a particular embodiment of the compound of formula (III), Gb is an oxygen atom and Rb is an alkyl group (Cl - C6) substituted by a -COORc group, where Rc represents a hydrogen atom or a group (Cl - 04) straight or branched unsubstituted alkyl.
[0035] Em uma modalidade particular do composto de[0035] In a particular modality of the compound of
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21/7021/70
fórmula (III) é selecionado no grupo que consiste em l—[4— metiltiofenil]-3-[3,5-dimetil-4-carboxidimetilmetiloxi fenil]prop-2-en-l-ona (Elafibranor ou GFT505), l—[4— metiltiofenil]-3-[3,5-dimetil-4-isopropiloxi carbonildimetilmetiloxifenil]prop-2-en-l-ona, 1-[4metiltiofenil]-3-[3,5-dimetil-4-tercbutiloxicarbonildimetilmetiloxifenil] prop-2-en-l-ona, 1[4-trifluorometilfenil]-3-[3,5-dimetil-4-tercbutiloxicarbonil dimetilmetiloxifenil]prop-2-en-l-ona, 1[4-trifluorometilfenil]-3-[3,5-dimetil-4carboxidimetilmetiloxifenil]prop-2-en-l-ona, 1-[4trifluorometil oxifenil]-3-[3,5-dimetil-4-tercbutiloxicarbonildimetilmetiloxi fenil] prop-2-en-1-ona, 1[ 4-trifluorometiloxifenil]-3-[3,5-dimetil-4carboxidimetilmetil oxifenil]prop-2-en-l-ona, ácido 2-[2,6dimetil-4-[3-[4-(metiltio)fenil]-3-oxo-propil] fenoxi]-2metilpropanoico e éster isopropilico de ácido 2-[2,6dimetil-4-[3-[4-(metiltio) fenil]-3-oxo-propil]fenoxi]-2metil-propanoico.formula (III) is selected from the group consisting of l— [4— methylthiophenyl] -3- [3,5-dimethyl-4-carboxidimethylmethyloxy phenyl] prop-2-en-l-one (Elafibranor or GFT505), l— [4— methylthiophenyl] -3- [3,5-dimethyl-4-isopropyloxy carbonyldimethylmethyloxyphenyl] prop-2-en-l-one, 1- [4methylthiophenyl] -3- [3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl] prop -2-en-l-one, 1 [4-trifluoromethylphenyl] -3- [3,5-dimethyl-4-tertbutyloxycarbonyl dimethylmethyloxyphenyl] prop-2-en-l-one, 1 [4-trifluoromethylphenyl] -3- [ 3,5-dimethyl-4carboxidimethylmethyloxyphenyl] prop-2-en-l-one, 1- [4trifluoromethyl oxyphenyl] -3- [3,5-dimethyl-4-tertbutyloxycarbonildimethylmethyloxy phenyl] prop-2-en-1-one, 1 [4-trifluoromethyloxyphenyl] -3- [3,5-dimethyl-4carboxidimethylmethyl oxyphenyl] prop-2-en-l-one, 2- [2,6dimethyl-4- [3- [4- (methylthio) phenyl] - acid 3-oxo-propyl] phenoxy] -2-methylpropanoic and 2- [2,6dimethyl-4- [3- [4- (methylthio) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid isopropyl ester.
[0037] Em uma modalidade mais particular, o agonista de PPAR é 1-[ 4-metiltiofenil]-3-[3,5-dimetil-4carboxidimetilmetiloxi fenil]prop-2-en-l-ona (ou[0037] In a more particular embodiment, the PPAR agonist is 1- [4-methylthiophenyl] -3- [3,5-dimethyl-4carboxidimethylmethyloxy phenyl] prop-2-en-l-one (or
Elafibranor - GFT505) ou um sal farmaceuticamente aceitável do mesmo.Elafibranor - GFT505) or a pharmaceutically acceptable salt thereof.
[0038] Em uma modalidade particular do produto de[0038] In a particular modality of the product of
Petição 870190071527, de 26/07/2019, pág. 36/109Petition 870190071527, of 7/26/2019, p. 10/36
22/70 combinação da invenção:22/70 combination of the invention:
[0039] - o componente (ii) é selecionado a partir do grupo que consiste em Elafibranor, Saroglitazar, Seladelpar e Lanifibranor, sendo o componente (ii) mais particularmente Elafibranor;[0039] - component (ii) is selected from the group consisting of Elafibranor, Saroglitazar, Seladelpar and Lanifibranor, with component (ii) being more particularly Elafibranor;
[0040] - o componente (i) é selecionado a partir de NTZ, TZ, 2-(d3) etanoato de [(5-nitro-l,3-tiazol-2il) carbamoil]fenila, (d2) etanoato de 2-[(5-nitro-l,3tiazol-2-il)carbamoil]fenila, (dl) etanoato de 2-[(5-nitro1,3-tiazol-2-il)carbamoil]fenila, (cloridrato de 2-amino-[0040] - component (i) is selected from NTZ, TZ, 2- (d3) ethanoate of [(5-nitro-1,3-thiazol-2yl) carbamoyl] phenyl, (d2) ethanoate of 2- [(5-nitro-1,3-thiazol-2-yl) carbamoyl] phenyl, (dl) 2 - [(5-nitro1,3-thiazol-2-yl) carbamoyl] phenyl, phenyl, (2-amino- hydrochloride
[0041] Em uma modalidade adicional, o componente (i) é selecionado a partir de TZG, 2-amino-3,3-dimetilbutanoato de 2-(5-nitrotiazol-2-ilcarbamoil)fenila (como 2-amino-3,3dimetilbutanoato de (S)-2-(5-nitrotiazol-2ilcarbamoil)fenila ou seu sal de cloridrato), 2-amino-3metilpentanoato de 2-(5-nitrotiazol-2-ilcarbamoil)fenila (como 2-amino-3-metilpentanoato de (2S,3S)-2-(5nitrotiazol-2-ilcarbamoil)fenila ou seu sal de cloridrato), 2-amino-3,3-dimetilbutanoato de 2-(5-clorotiazol-2ilcarbamoil)fenila (como 2-amino-3,3-dimetilbutanoato de (S)-2-(5-clorotiazol-2-ilcarbamoil)fenila ou seu sal de cloridrato), e 2-amino-3-metilpentanoato de 2—(5— clorotiazol-2-ilcarbamoil)fenila (como 2-amino-3metilpentanoato de (2S,3S)-2-(5-clorotiazol-2ilcarbamoil)fenila ou seu sal de cloridrato). Em uma variante adicional dessa modalidade, o componente (ii) é[0041] In an additional embodiment, component (i) is selected from TZG, 2- (5-nitrothiazol-2-ylcarbamoyl) phenyl (as 2-amino-3, 2-amino-3,3-dimethylbutanoate) (S) -2- (5-nitrothiazol-2ylcarbamoyl) phenyl or its hydrochloride salt, 2- (5-nitrothiazol-2-ylcarbamoyl) phenyl (as 2-amino-3-methylpentanoate) 2-amino-3-methylpentanoate of (2S, 3S) -2- (5nitrothiazol-2-ylcarbamoyl) phenyl or its hydrochloride salt), 2- (5-chlorothiazole-2ylcarbamoyl) 2-amino-3,3-dimethylbutanoate (as 2-amino- (S) -2- (5-chlorothiazol-2-ylcarbamoyl) phenyl 3,3-dimethylbutanoate or its hydrochloride salt), and 2— (5— chlorothiazol-2-ylcarbamoyl) phenyl 2-amino-3-methylpentanoate (such as (2S, 3S) -2- (5-chlorothiazole-2ylcarbamoyl) 2-amino-3methylpentanoate) phenyl or its hydrochloride salt). In an additional variant of this modality, component (ii) is
Petição 870190071527, de 26/07/2019, pág. 37/109Petition 870190071527, of 7/26/2019, p. 37/109
23/70 selecionado a partir do grupo que consiste em Elafibranor, Saroglitazar Seladelpar e Lanifibranor, sendo o componente (ii) mais particularmente Elafibranor; e o componente (i) é selecionado a partir de TZG, 2-amino-3,3-dimetilbutanoato de 2-(5-nitrotiazol-2-ilcarbamoil)fenila (como 2-amino-3,3dimetilbutanoato de (S)-2-(5-nitrotiazol-2ilcarbamoil)fenila ou seu sal de cloridrato), 2-amino-3metilpentanoato de 2-(5-nitrotiazol-2-ilcarbamoil)fenila (como 2-amino-3-metilpentanoato de (2S,3S)-2-(5nitrotiazol-2-ilcarbamoil)fenila ou seu sal de cloridrato), 2-amino-3,3-dimetilbutanoato de 2-(5-clorotiazol-2ilcarbamoil)fenila (como 2-amino-3,3-dimetilbutanoato de (S)-2-(5-clorotiazol-2-ilcarbamoil)fenila ou seu sal de cloridrato), e 2-amino-3-metilpentanoato de 2—(5— clorotiazol-2-ilcarbamoil)fenila (como 2-amino-3metilpentanoato de (2S,3S)-2-(5-clorotiazol-2ilcarbamoil)fenila ou seu sal de cloridrato).23/70 selected from the group consisting of Elafibranor, Saroglitazar Seladelpar and Lanifibranor, with component (ii) being more particularly Elafibranor; and component (i) is selected from 2- (5-nitrothiazol-2-ylcarbamoyl) phenyl 2-amino-3,3-dimethylbutanoate (as (S) -2 2-amino-3,3-dimethylbutanoate - 2- (5-nitrothiazol-2-ylcarbamoyl) (5-nitrothiazol-2ylcarbamoyl) phenyl or its hydrochloride salt (2S, 3S) 2- (5-nitrothiazol-2-ylcarbamoyl) phenyl (as 2S, 3S) 2-amino-3-methylpentanoate - 2- (5-nitrothiazol-2-ylcarbamoyl) phenyl or its hydrochloride salt, 2- (5-chlorothiazol-2ylcarbamoyl) 2-amino-3,3-dimethylbutanoate (such as (2-amino-3,3-dimethylbutanoate) S) -2- (5-chlorothiazol-2-ylcarbamoyl) phenyl or its hydrochloride salt), and 2— (5— chlorothiazol-2-ylcarbamoyl) 2-amino-3-methylpentanoate (as 2-amino-3methylpentanoate (2S, 3S) -2- (5-chlorothiazole-2ylcarbamoyl) phenyl or its hydrochloride salt).
[0042] Em uma modalidade particular, o produto de combinação da invenção compreende adicionalmente pelo menos um outro agente terapeuticamente ativo como um agente antifibrótico, um agente anti-inflamatório ou um agente imunossupressor.[0042] In a particular embodiment, the combination product of the invention additionally comprises at least one other therapeutically active agent such as an antifibrotic agent, an anti-inflammatory agent or an immunosuppressive agent.
[0043] Os agentes antifibróticos exemplificativos incluem pirfenidona ou inibidores de receptor tirosina quinase (RTKIs) como Nintedanibe, Sorafenibe e outros RTKIs, ou bloqueadores de receptor de angiotensina II (ATI), ou inibidor de CTGF, ou qualquer composto antifibrótico suscetível a interferir com as vias ativadas por TGFp e BMP incluindo ativadores do complexo de TGFp latente como MMP2, MMP9, THBS1 ou integrinas de superfícieExemplary antifibrotic agents include pirfenidone or tyrosine kinase receptor inhibitors (RTKIs) such as Nintedanib, Sorafenib and other RTKIs, or angiotensin II receptor blockers (ATI), or CTGF inhibitor, or any antifibrotic compound susceptible to interfere with pathways activated by TGFp and BMP including activators of the latent TGFp complex such as MMP2, MMP9, THBS1 or surface integrins
Petição 870190071527, de 26/07/2019, pág. 38/109Petition 870190071527, of 7/26/2019, p. 38/109
24/70 celular, receptores de TGFp tipo I (TGFBRI) ou tipo II (TGFBRII) e seus ligantes como TGFp, Activina, inibina, Nodal, hormônio antimülleriano, GDFs ou BMPs, correceptores auxiliares (também conhecidos como receptores tipo III), ou componentes da via canônica dependente de SMAD incluindo proteínas SMAD regulatórias ou inibitórias, ou membros das vias não canônicas ou independentes de SMAD incluindo várias ramificações de sinalização de MAPK, TAK1, vias de sinalização de GTPase do tipo Rho, vias de fosfatidilinositol-3 quinase/AKT, processo de EMT induzido por TGFp, ou vias de sinalização Hedgehog canônicas ou não canônicas incluindo ligantes de Hh ou genes-alvo, ou quaisquer membros do WNT, ou vias Notch que são suscetíveis a influenciar TGFp .24/70 cell, TGFp type I (TGFBRI) or type II (TGFBRII) receptors and their ligands such as TGFp, Activin, inhibin, Nodal, anti-Müllerian hormone, GDFs or BMPs, auxiliary co-receptors (also known as type III receptors), or components of the SMAD-dependent canonical pathway including regulatory or inhibitory SMAD proteins, or members of the non-canonical or SMAD-independent pathways including various MAPK, TAK1 signaling branches, Rho GTPase signaling pathways, phosphatidylinositol-3 kinase pathways / AKT, TGFp-induced EMT process, or canonical or non-canonical Hedgehog signaling pathways including Hh ligands or target genes, or any members of the WNT, or Notch pathways that are susceptible to influencing TGFp.
[0044] Os agentes anti-inflamatórios e/ou agentes imunossupressores ilustrativos incluem glicocorticoides, NSAIDS, ciclofosfamida, nitrosoureias, análogos de ácido fólico, análogos de purina, análogos de pirimidina, metotrexato, azatioprina, mercaptopurina, ciclosporina, miriocina, tacrolimo, sirolimo, derivados de ácido micofenólico, fingolimod e outros moduladores de receptor de esfingosina-l-fosfato, anticorpos monoclonais e/ou policlonais contra tais alvos como citocinas próinflamatórias e receptores de citocina pró-inflamatória, receptor de célula T e integrinas.Illustrative anti-inflammatory agents and / or immunosuppressive agents include glucocorticoids, NSAIDS, cyclophosphamide, nitrosoureas, folic acid analogs, purine analogs, pyrimidine analogs, methotrexate, azathioprine, mercaptopurine, cyclosporine, myocardine, tyrolol, tyrolol mycophenolic acid derivatives, fingolimod and other sphingosine-1-phosphate receptor modulators, monoclonal and / or polyclonal antibodies against such targets as proinflammatory cytokines and proinflammatory cytokine receptors, T cell receptor and integrins.
[0045] Em uma modalidade particular, o produto de combinação da invenção é uma composição que compreende os componentes (i) e (ii) como descrito acima, e um carreador farmaceuticamente aceitável.[0045] In a particular embodiment, the combination product of the invention is a composition comprising components (i) and (ii) as described above, and a pharmaceutically acceptable carrier.
[0046] Em uma modalidade particular, o produto de[0046] In a particular modality, the product of
Petição 870190071527, de 26/07/2019, pág. 39/109Petition 870190071527, of 7/26/2019, p. 10/39
25/70 combinação é um kit de partes que compreende os componentes (i) e (ii) como descrito acima, para uso sequencial, separado ou simultâneo.25/70 combination is a kit of parts comprising components (i) and (ii) as described above, for sequential, separate or simultaneous use.
[0047] Em uma modalidade adicional, os componentes i) e ii) são formulados em uma suspensão injetável, um gel, um óleo, uma pílula, um comprimido, um supositório, um pó, uma cápsula, um aerossol, uma pomada, um creme, um emplastro ou meios de formas galênicas para uma liberação prolongada e/ou lenta.[0047] In an additional embodiment, components i) and ii) are formulated in a suspension for injection, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, an ointment, an cream, a plaster or galenic forms means for a prolonged and / or slow release.
[0048] Em uma outra modalidade, os componentes (i) e (ii) do produto de combinação são usados no tratamento de qualquer uma das doenças mencionadas acima.[0048] In another embodiment, the components (i) and (ii) of the combination product are used in the treatment of any of the diseases mentioned above.
[0049] A presente invenção também se refere ao produto de combinação de acordo com a invenção, para uso como um medicamento.[0049] The present invention also relates to the combination product according to the invention, for use as a medicament.
[0050] A invenção também se refere ao produto de combinação revelado no presente documento, para uso em um método para o tratamento da doença. Em uma outra modalidade, a invenção se refere a um método para o tratamento de uma doença, que compreende administrar a um indivíduo em necessidade do mesmo uma quantidade terapeuticamente eficaz do produto de combinação revelado no presente documento. Em uma outra modalidade, é fornecido o uso de um produto de combinação de acordo com a invenção, para a fabricação de um medicamento para o tratamento de uma doença.[0050] The invention also relates to the combination product disclosed herein, for use in a method for treating the disease. In another embodiment, the invention relates to a method for the treatment of a disease, which comprises administering to a subject in need thereof a therapeutically effective amount of the combination product disclosed herein. In another embodiment, the use of a combination product according to the invention is provided for the manufacture of a medicament for the treatment of a disease.
[0051] Em particular, o produto de combinação da presente invenção é útil para o tratamento de doenças como doenças imunes, inflamatórias, metabólicas, fibróticas e colestáticas. Em uma modalidade particular, a doença é[0051] In particular, the combination product of the present invention is useful for the treatment of diseases such as immune, inflammatory, metabolic, fibrotic and cholestatic diseases. In a particular modality, the disease is
Petição 870190071527, de 26/07/2019, pág. 40/109Petition 870190071527, of 7/26/2019, p. 10/40
26/70 selecionada a partir do grupo que consiste em doenças hepáticas metabólicas, doença hepática gordurosa não alcoólica (NAFLD), esteato-hepatite não alcoólica (NASH), doenças hepáticas induzidas por drogas, doenças hepáticas induzidas por álcool, doenças hepáticas induzidas por agente infeccioso, doenças hepáticas inflamatórias, doenças hepáticas mediadas por disfunção do sistema imunológico, dislipidemia, doenças cardiovasculares, restenose, síndrome X, síndrome metabólica, diabetes, obesidade, hipertensão, colangiopatias crônicas como Colangite Esclerosante Primária (PSC), Colangite Biliar Primária (PBC), atresia biliar, colestase intra-hepática familiar tipo 3 (PFIC3), doenças inflamatórias intestinais, doença de Crohn, colite ulcerativa, queloide, infarto do miocárdio, escleroderma/esclerose sistêmica, doenças inflamatórias, doenças neurodegenerativas, cânceres, câncer hepático, carcinoma hepatocelular, câncer gastrointestinal, câncer gástrico, meningioma associado à neurofibromatose, tumores neuroendócrinos pancreáticos, tumores exócrinos pancreáticos, leucemia, doenças de mieloproliferativas/mielodisplásicas, mastoeitose, dermatofibrossarcoma, tumores sólidos incluindo câncer de mama, pulmão, tireoide ou colorretal, um câncer de próstata, fibrose ou cirrose hepática de qualquer origem, fibrose ou cirrose hepática induzida por doença metabólica, fibrose ou cirrose induzida por NAFLD, fibrose ou cirrose induzida por NASH, fibrose ou cirrose hepática induzida por álcool, fibrose ou cirrose hepática induzida por drogas, fibrose ou cirrose hepática induzida por agente infeccioso, fibrose ou cirrose hepática induzida por infecção por26/70 selected from the group consisting of metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, agent-induced liver disease infectious, inflammatory liver disease, liver disease mediated by immune system dysfunction, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC), Primary Biliary Cholangitis (PBC) , biliary atresia, familial type 3 intrahepatic cholestasis (PFIC3), inflammatory bowel disease, Crohn's disease, ulcerative colitis, keloid, myocardial infarction, scleroderma / systemic sclerosis, inflammatory diseases, neurodegenerative diseases, cancers, liver cancer, hepatocellular carcinoma , gastrointestinal cancer, gastric cancer, neurofiber-associated meningioma matose, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, myeloproliferative / myelodysplastic diseases, mastoeitosis, dermatofibrosarcoma, solid tumors including breast, lung, thyroid or colorectal cancer, prostate cancer, fibrosis or any liver disease metabolic disease-induced liver cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced fibrosis or liver cirrhosis, drug-induced fibrosis or liver cirrhosis induced by infectious agent, fibrosis or liver cirrhosis induced by infection by
Petição 870190071527, de 26/07/2019, pág. 41/109Petition 870190071527, of 7/26/2019, p. 41/109
27/70 parasita, fibrose ou cirrose hepática induzida por infecção bacteriana, fibrose ou cirrose induzida por infecção viral,27/70 parasite, fibrosis or liver cirrhosis induced by bacterial infection, fibrosis or cirrhosis induced by viral infection,
quimioterapia, fibrose do trato biliar, fibrose ou cirrose hepática devido a qualquer doença colestática crônica, fibrose intestinal de qualquer etiologia, fibrose induzida por doença de Crohn, fibrose induzida por colite ulcerativa, fibrose do intestino (por exemplo, intestino delgado), fibrose de cólon, fibrose de estômago, fibrose cutânea, fibrose da epiderme, fibrose da endoderme, fibrose cutânea devido à escleroderma/esclerose sistêmica, fibrose pulmonar, fibrose consecutiva a doenças inflamatórias crônicas das vias aéreas, como COPD, asma, enfisema, pulmão de fumante, tuberculose, fibrose pulmonar, fibrose pulmonar idiopática (IPF), fibrose cardíaca, fibrose renal, fibrose sistêmica nefrogênica, fibrose muscular, fibrose de tecido mole (por exemplo, mediastino ou retroperitônio) fibrose, fibrose de medula óssea, fibrose de junta, fibrose de tendão, fibrose de cartilagem, fibrose de pâncreas, fibrose de útero, fibrose do sistema nervoso, fibrose do testículo, fibrose do ovário, fibrose da glândula adrenal, fibrose arterial, fibrose venosa, fibrose ocular, fibrose endomiocardial, fibrose mediastinal, mielofibrose, fibrose retroperitoneal, fibrose massiva progressiva (uma complicação de pneumoconiose de pessoas que trabalham com carvão), fibrose proliferativa, fibrose neoplásica, fibrosechemotherapy, fibrosis of the biliary tract, fibrosis or liver cirrhosis due to any chronic cholestatic disease, intestinal fibrosis of any etiology, fibrosis induced by Crohn's disease, fibrosis induced by ulcerative colitis, fibrosis of the intestine (eg small intestine), fibrosis of colon, stomach fibrosis, cutaneous fibrosis, fibrosis of the epidermis, fibrosis of the endodermis, fibrosis due to scleroderma / systemic sclerosis, pulmonary fibrosis, fibrosis following chronic inflammatory diseases of the airways, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, renal fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue fibrosis (for example, mediastinum or retroperitoneum) fibrosis, bone marrow fibrosis, joint fibrosis, fibrosis of tendon, cartilage fibrosis, pancreas fibrosis, fibrosis of the uterus, fibrosis of the nervous system, fibrosis of the testis, fibrosis of the ovary, fi adrenal gland brose, arterial fibrosis, venous fibrosis, ocular fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of pneumoconiosis in people who work with coal), proliferative fibrosis, neoplastic fibrosis, fibrosis
Petição 870190071527, de 26/07/2019, pág. 42/109Petition 870190071527, of 7/26/2019, p. 42/109
28/70 peri-implante e asbestose, artrofibrose, capsulite adesiva. [0052] Em uma modalidade de máxima preferência, a doença é selecionada a partir do grupo que consiste em doenças hepáticas metabólicas, doença hepática gordurosa não alcoólica (NAFLD), esteato-hepatite não alcoólica (NASH), doenças hepáticas induzidas por drogas, doenças hepáticas induzidas por álcool, doenças hepáticas induzidas por agente infeccioso, doenças hepáticas inflamatórias, doenças hepáticas mediadas por disfunção do sistema imunológico, dislipidemia, doenças cardiovasculares, restenose, sindrome X, sindrome metabólica, diabetes, obesidade, hipertensão, colangiopatias crônicas como Colangite Esclerosante Primária (PSC), Colangite Biliar Primária (PBC), atresia biliar, colestase intra-hepática familiar tipo 3 (PFIC3), doenças inflamatórias intestinais, doença de Crohn, colite ulcerativa, câncer hepático, carcinoma hepatocelular, câncer gastrointestinal, câncer gástrico, câncer colorretal, fibrose ou cirrose hepática induzida por doença metabólica, fibrose ou cirrose induzida por NAFLD, fibrose ou cirrose induzida por NASH, fibrose ou cirrose hepática induzida por álcool, fibrose ou cirrose hepática induzida por drogas, fibrose ou cirrose hepática induzida por agente infeccioso, fibrose ou cirrose hepática induzida por infecção por parasita, fibrose ou cirrose hepática induzida28/70 peri-implant and asbestosis, arthrofibrosis, adhesive capsulitis. [0052] In a form of maximum preference, the disease is selected from the group consisting of metabolic liver diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver diseases, diseases alcohol-induced liver disease, infectious agent-induced liver disease, inflammatory liver disease, immune-mediated liver disease, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC), Primary Biliary Cholangitis (PBC), biliary atresia, familial type 3 intrahepatic cholestasis (PFIC3), inflammatory bowel disease, Crohn's disease, ulcerative colitis, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, colorectal cancer , fibrosis or liver cirrhosis induced by metabolic disease, fibrosis or induced cirrhosis NAFLD, NASH-induced fibrosis or cirrhosis, alcohol-induced fibrosis or liver cirrhosis, drug-induced fibrosis or liver cirrhosis, infectious agent-induced liver fibrosis, liver fibrosis or liver cirrhosis induced by parasite infection, fibrosis or liver cirrhosis induced
Petição 870190071527, de 26/07/2019, pág. 43/109Petition 870190071527, of 7/26/2019, p. 43/109
29/70 por radiação ou quimioterapia, fibrose do trato biliar, fibrose ou cirrose hepática devido a qualquer doença colestática crônica, fibrose intestinal de qualquer etiologia, fibrose induzida por doença de Crohn, fibrose induzida por colite ulcerativa, fibrose do intestino (por exemplo, intestino delgado), fibrose de cólon, fibrose de estômago, fibrose pulmonar, fibrose consecutiva a doenças inflamatórias crônicas das vias aéreas, como COPD, asma, enfisema, pulmão de fumante, tuberculose, fibrose pulmonar, fibrose pulmonar idiopática (IPF).29/70 by radiation or chemotherapy, fibrosis of the biliary tract, fibrosis or liver cirrhosis due to any chronic cholestatic disease, intestinal fibrosis of any etiology, fibrosis induced by Crohn's disease, fibrosis induced by ulcerative colitis, intestinal fibrosis (for example, small intestine), colon fibrosis, stomach fibrosis, pulmonary fibrosis, fibrosis following chronic inflammatory diseases of the airways, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF).
[0053] Em um aspecto adicional, a invenção se refere à combinação da invenção para uso na inibição de proliferação e/ou ativação de fibroblastos responsáveis pela produção de fibras de colágeno e/ou responsáveis pela produção da matriz extracelular.[0053] In a further aspect, the invention relates to the combination of the invention for use in the inhibition of proliferation and / or activation of fibroblasts responsible for the production of collagen fibers and / or responsible for the production of the extracellular matrix.
[0054] De acordo com a presente invenção, o termo doenças autoimunes é usado para designar uma condição que surge a partir de um resposta imune anormal do corpo contra substâncias e tecidos normalmente presentes no corpo. A doença pode ser restringida a certos órgãos (por exemplo, em diabetes tipo I ou tireoidite autoimune) ou envolve um tecido particular em lugares diferentes (por exemplo, em doença de Goodpasture, condição da membrana basal no pulmão e no rim).[0054] According to the present invention, the term autoimmune diseases is used to designate a condition that arises from an abnormal immune response in the body against substances and tissues normally present in the body. The disease can be restricted to certain organs (for example, in type I diabetes or autoimmune thyroiditis) or involves a particular tissue in different places (for example, in Goodpasture's disease, condition of the basement membrane in the lung and kidney).
[0055] 0 termo inflamação é usado para designar uma condição que surge a partir de uma resposta protetora que envolve células hospedeiras, vasos sanguíneos, e proteínas e outros mediadores que podem servir para eliminar a causa de lesão de célula/tecido, assim como as células/os tecidos necróticos resultantes do insulto original e para iniciar o[0055] The term inflammation is used to designate a condition that arises from a protective response that involves host cells, blood vessels, and proteins and other mediators that can serve to eliminate the cause of cell / tissue damage, as well as necrotic cells / tissues resulting from the original insult and to initiate the
Petição 870190071527, de 26/07/2019, pág. 44/109Petition 870190071527, of 7/26/2019, p. 44/109
30/70 processo de reparo. A reação inflamatória pode ser manifestada por dor, calor, vermelhidão, inchaço, dilatação de vasos sanguíneos, aumento do fluxo sanguíneo e perda de função.30/70 repair process. The inflammatory reaction can be manifested by pain, heat, redness, swelling, dilation of blood vessels, increased blood flow and loss of function.
[0056] Os termos fibrose, doença fibrótica, transtorno fibrótico e declinações do mesmo denotam uma condição patológica de deposição excessiva de tecido conjuntivo fibroso em um órgão ou tecido. Mais especificamente, a fibrose é um processo patológico, que inclui um formação de cicatriz fibrótica persistente e superprodução de matriz extracelular, pelo tecido conjuntivo, como uma resposta à danificação de tecido. Fisiologicamente, o deposito de tecido conjuntivo pode obliterar a arquitetura e a função do órgão ou tecido subj acente.[0056] The terms fibrosis, fibrotic disease, fibrotic disorder and declines thereof denote a pathological condition of excessive deposition of fibrous connective tissue in an organ or tissue. More specifically, fibrosis is a pathological process, which includes the formation of a persistent fibrotic scar and overproduction of extracellular matrix, by the connective tissue, as a response to tissue damage. Physiologically, the deposit of connective tissue can obliterate the architecture and function of the underlying organ or tissue.
[0057] De acordo com a presente invenção, a fibrose ou transtorno fibrótico pode ser associado a qualquer fibrose de órgão ou tecido. Os exemplos ilustrativos não limitantes de fibrose de órgão particular incluem fibrose do fígado, rim, pele, epiderme, endoderme, músculo, tendão, cartilagem, coração, pâncreas, pulmão, útero, sistema nervoso, testículo, pênis, ovário, glândula adrenal, artéria, veia, cólon, intestino (por exemplo, intestino delgado), trato biliar, tecido mole (por exemplo, mediastino ou retroperitônio) , medula óssea, junta (por exemplo, joelho, ombro ou outras juntas) ou estômago.[0057] According to the present invention, fibrosis or fibrotic disorder can be associated with any organ or tissue fibrosis. Non-limiting illustrative examples of particular organ fibrosis include fibrosis of the liver, kidney, skin, epidermis, endoderm, muscle, tendon, cartilage, heart, pancreas, lung, uterus, nervous system, testis, penis, ovary, adrenal gland, artery , vein, colon, intestine (for example, small intestine), biliary tract, soft tissue (for example, mediastinum or retroperitoneum), bone marrow, joint (for example, knee, shoulder or other joints) or stomach.
[0058] Em uma modalidade particular, o transtorno fibrótico é selecionado a partir do grupo que consiste em uma fibrose do fígado, rim, pele, epiderme, endoderme, músculo, tendão, cartilagem, coração, pâncreas, pulmão,[0058] In a particular embodiment, fibrotic disorder is selected from the group consisting of fibrosis of the liver, kidney, skin, epidermis, endoderm, muscle, tendon, cartilage, heart, pancreas, lung,
Petição 870190071527, de 26/07/2019, pág. 45/109Petition 870190071527, of 7/26/2019, p. 45/109
31/70 útero, sistema nervoso, testículo, ovário, glândula adrenal, artéria, veia, cólon, intestino (por exemplo, intestino delgado), trato biliar, tecido mole (por exemplo, mediastino ou retroperitônio), medula óssea, junta (por exemplo, joelho, ombro ou outras juntas), olho ou estômago. [0059] Em uma modalidade preferencial, o transtorno fibrótico é selecionado a partir do grupo que consiste em uma fibrose do fígado, intestinos, pulmão, coração, rim, músculo, pele, tecido mole (por exemplo, mediastino ou retroperitônio), medula óssea, intestinal e junta (por exemplo, joelho, ombro ou outras juntas).31/70 uterus, nervous system, testis, ovary, adrenal gland, artery, vein, colon, intestine (eg, small intestine), biliary tract, soft tissue (eg, mediastinum or retroperitoneum), bone marrow, joint (by knee, shoulder or other joints), eye or stomach. [0059] In a preferred embodiment, the fibrotic disorder is selected from the group consisting of fibrosis of the liver, intestines, lung, heart, kidney, muscle, skin, soft tissue (eg, mediastinum or retroperitoneum), bone marrow , intestinal and joint (for example, knee, shoulder or other joints).
[0060] Em uma modalidade mais preferencial, o transtorno fibrótico é selecionado a partir do grupo que consiste em fibrose do fígado, pulmão, intestinal, coração, pele, rim e intestinal.[0060] In a more preferred modality, fibrotic disorder is selected from the group consisting of fibrosis of the liver, lung, intestinal, heart, skin, kidney and intestinal.
[0061] Em uma outra modalidade, o transtorno fibrótico é selecionado a partir do grupo que consiste em fibrose do fígado, pulmão, coração e intestinal. Em uma modalidade mais particular, o transtorno fibrótico é selecionado a partir do grupo que consiste em fibrose do fígado, pulmão, pele, rim e intestinal. Em uma outra modalidade, o transtorno fibrótico é fibrose do fígado.[0061] In another modality, fibrotic disorder is selected from the group consisting of fibrosis of the liver, lung, heart and intestine. In a more particular modality, fibrotic disorder is selected from the group consisting of fibrosis of the liver, lung, skin, kidney and intestine. In another embodiment, the fibrotic disorder is fibrosis of the liver.
[0062] Em uma modalidade mais preferencial da presente invenção, o transtorno fibrótico tratado é selecionado a partir do grupo que consiste na seguinte lista não aprofundada de transtornos fibróticos: esteato-hepatite não alcoólica (NASH), fibrose pulmonar, fibrose pulmonar idiopática, fibrose cutânea, fibrose ocular (como fibrose capsular), fibrose endomiocardial, fibrose mediastinal, mielofibrose, fibrose retroperitoneal, fibrose massiva[0062] In a more preferred embodiment of the present invention, the treated fibrotic disorder is selected from the group consisting of the following in-depth list of fibrotic disorders: non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, idiopathic pulmonary fibrosis, fibrosis cutaneous, ocular fibrosis (such as capsular fibrosis), endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, massive fibrosis
Petição 870190071527, de 26/07/2019, pág. 46/109Petition 870190071527, of 7/26/2019, p. 46/109
32/70 progressiva (uma complicação de pneumoconiose de pessoas que trabalham com carvão), fibrose proliferativa, fibrose neoplásica, fibrose pulmonar consecutiva à doença inflamatória das vias aéreas crônica (COPD, asma, enfisema, pulmão de fumante, tuberculose, IPF), fibrose hepática induzida por álcool ou drogas, cirrose hepática, fibrose hepática induzida por infecção, fibrose induzida por radiação ou quimioterapia, fibrose sistêmica nefrogênica, doença de Crohn, colite ulcerativa, queloide, infarto do miocárdio, escleroderma/esclerose sistêmica, artrofibrose, algumas de capsulite adesiva, colangiopatias fibrosantes crônicas como Colangite Esclerosante Primária (PSC) e Colangite Biliar Primária (PBC), atresia biliar, colestase intra-hepática familiar tipo 3 (PFIC3), fibrose periimplante e asbestose.Progressive 32/70 (a complication of pneumoconiosis in people who work with coal), proliferative fibrosis, neoplastic fibrosis, pulmonary fibrosis following chronic inflammatory airway disease (COPD, asthma, emphysema, smoker's lung, tuberculosis, IPF), fibrosis alcohol or drug-induced liver disease, liver cirrhosis, infection-induced liver fibrosis, radiation-induced fibrosis or chemotherapy, nephrogenic systemic fibrosis, Crohn's disease, ulcerative colitis, keloid, myocardial infarction, scleroderma / systemic sclerosis, arthrofibrosis, some of capsulitis adhesive, chronic fibrous cholangiopathies such as Primary Sclerosing Cholangitis (PSC) and Primary Biliary Cholangitis (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3), peri-implant fibrosis and asbestosis.
[0063] A colestase é definida como uma diminuição no fluxo de bile devido à secreção prejudicada por hepatócitos (colestase hepatocelular) ou à obstrução de fluxo de bile através de dutos de bile intra- ou extra-hepáticos (colestase obstrutiva). Na prática clínica, a colestase é qualquer condição em que o fluxo de bile do fígado é retardado ou bloqueado. De acordo com uma modalidade particular da invenção, a doença colestática é selecionada a partir do grupo que consiste em Colangite Biliar Primária (PBC), Colangite Esclerosante Primária (PSC), Colestase Inter-hepática de Gravidez (ICP), Colestase Intra-hepática Familiar Progressiva (PFIC), Atresia Biliar, Colelitiase, colangite infecciosa, Colangite associada à histiocitose celular de Langerhans, síndrome de Alagille, paucidade dutal não sindrômica, colestase induzida por drogas e[0063] Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes (hepatocellular cholestasis) or obstruction of bile flow through intra- or extrahepatic bile ducts (obstructive cholestasis). In clinical practice, cholestasis is any condition in which the flow of bile from the liver is slowed or blocked. In accordance with a particular embodiment of the invention, cholestatic disease is selected from the group consisting of Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Interhepatic Pregnancy Cholestasis (PCI), Familial Intrahepatic Cholestasis Progressive (PFIC), Biliary Atresia, Cholelithiasis, infectious cholangitis, Cholangitis associated with Langerhans cell histiocytosis, Alagille syndrome, non-syndromic northern paucity, drug-induced cholestasis and
Petição 870190071527, de 26/07/2019, pág. 47/109Petition 870190071527, of 7/26/2019, p. 47/109
33/70 colestase associada à nutrição parenteral total. Em uma modalidade preferencial, a doença colestática é PBC ou PSC, em particular, PBC.33/70 cholestasis associated with total parenteral nutrition. In a preferred embodiment, the cholestatic disease is PBC or PSC, in particular, PBC.
[0064] Os exemplos de doenças inflamatórias, doenças fibróticas, doenças metabólicas e doenças colestáticas incluem doenças hepáticas metabólicas, doença hepática gordurosa não alcoólica (NAFLD), esteato-hepatite não alcoólica (NASH), doenças hepáticas induzidas por drogas, doenças hepáticas induzidas por álcool, doenças hepáticas induzidas por agente infeccioso, doenças hepáticas inflamatórias, doenças hepáticas mediadas por disfunção do sistema imunológico, dislipidemia, doenças cardiovasculares, restenose, síndrome X, síndrome metabólica, diabetes, obesidade, hipertensão, colangiopatias crônicas como Colangite Esclerosante Primária (PSC), Colangite Biliar Primária (PBC), atresia biliar, colestase intra-hepática familiar tipo 3 (PFIC3), doenças inflamatórias intestinais, doença de Crohn, colite ulcerativa, queloide, infarto do miocárdio, escleroderma/esclerose sistêmica, doenças inflamatórias, doenças neurodegenerativas, cânceres, câncer hepático, carcinoma hepatocelular, câncer gastrointestinal, câncer gástrico, meningioma associado à neurofibromatose, tumores neuroendócrinos pancreáticos, tumores exócrinos pancreáticos, leucemia, doenças de mieloproliferativas/mielodisplásicas, mastoeitose, dermatofibrossarcoma, tumores sólidos incluindo câncer de mama, pulmão, tireoide ou colorretal, um câncer de próstata, fibrose ou cirrose hepática de qualquer origem, fibrose ou cirrose hepática induzida por doença metabólica,[0064] Examples of inflammatory diseases, fibrotic diseases, metabolic diseases and cholestatic diseases include metabolic liver diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver diseases, liver diseases induced by alcohol, infectious agent-induced liver disease, inflammatory liver disease, liver disease mediated by immune system dysfunction, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC) , Primary Biliary Cholangitis (PBC), biliary atresia, familial type 3 intrahepatic cholestasis (PFIC3), inflammatory bowel disease, Crohn's disease, ulcerative colitis, keloid, myocardial infarction, systemic scleroderma / sclerosis, inflammatory diseases, neurodegenerative diseases, cancers, liver cancer, hepatocellular carcinoma, spent cancer rointestinal, gastric cancer, neurofibromatosis-associated meningioma, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, myeloproliferative / myelodysplastic diseases, mastoytosis, dermatofibrosarcoma, solid tumors including breast cancer, lung, or thyroid, thyroid or thyroid, thyroid, thyroid or thyroid disease liver cirrhosis of any origin, fibrosis or liver cirrhosis induced by metabolic disease,
Petição 870190071527, de 26/07/2019, pág. 48/109Petition 870190071527, of 7/26/2019, p. 48/109
34/70 fibrose ou cirrose induzida por NAFLD, fibrose ou cirrose induzida por NASH, fibrose ou cirrose hepática induzida por álcool, fibrose ou cirrose hepática induzida por drogas, fibrose ou cirrose hepática induzida por agente infeccioso, fibrose ou cirrose hepática induzida por infecção por parasita, fibrose ou cirrose hepática induzida por infecção bacteriana, fibrose ou cirrose induzida por infecção viral,34/70 NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced fibrosis or liver cirrhosis, drug-induced fibrosis or liver cirrhosis induced by infectious agent, fibrosis or liver cirrhosis induced by infection by parasite, fibrosis or liver cirrhosis induced by bacterial infection, fibrosis or cirrhosis induced by viral infection,
quimioterapia, fibrose do trato biliar, fibrose ou cirrose hepática devido a qualquer doença colestática crônica, fibrose intestinal de qualquer etiologia, fibrose induzida por doença de Crohn, fibrose induzida por colite ulcerativa, fibrose do intestino (por exemplo, intestino delgado), fibrose de cólon, fibrose de estômago, fibrose cutânea, fibrose da epiderme, fibrose da endoderme, fibrose cutânea devido à escleroderma/esclerose sistêmica, fibrose pulmonar, fibrose consecutiva a doenças inflamatórias crônicas das vias aéreas, como COPD, asma, enfisema, pulmão de fumante, tuberculose, fibrose pulmonar, fibrose pulmonar idiopática (IPF), fibrose cardíaca, fibrose renal, fibrose sistêmica nefrogênica, fibrose muscular, fibrose de tecido mole (por exemplo, mediastino ou retroperitônio) fibrose, fibrose de medula óssea, fibrose de junta, fibrose de tendão, fibrose de cartilagem, fibrose de pâncreas, fibrose de útero, fibrose do sistema nervoso, fibrose do testículo, fibrose do ovário, fibrose da glândula adrenal, fibrosechemotherapy, fibrosis of the biliary tract, fibrosis or liver cirrhosis due to any chronic cholestatic disease, intestinal fibrosis of any etiology, fibrosis induced by Crohn's disease, fibrosis induced by ulcerative colitis, fibrosis of the intestine (eg small intestine), fibrosis of colon, stomach fibrosis, cutaneous fibrosis, fibrosis of the epidermis, fibrosis of the endodermis, fibrosis due to scleroderma / systemic sclerosis, pulmonary fibrosis, fibrosis following chronic inflammatory diseases of the airways, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, renal fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue fibrosis (for example, mediastinum or retroperitoneum) fibrosis, bone marrow fibrosis, joint fibrosis, fibrosis of tendon, cartilage fibrosis, pancreas fibrosis, fibrosis of the uterus, fibrosis of the nervous system, fibrosis of the testis, fibrosis of the ovary, fi adrenal gland brose, fibrosis
Petição 870190071527, de 26/07/2019, pág. 49/109Petition 870190071527, of 7/26/2019, p. 10/49
35/70 arterial, fibrose venosa, fibrose ocular, fibrose endomiocardial, fibrose mediastinal, mielofibrose, fibrose retroperitoneal, fibrose massiva progressiva (uma complicação de pneumoconiose de pessoas que trabalham com carvão), fibrose proliferativa, fibrose neoplásica, fibrose peri-implante e asbestose, artrofibrose, capsulite adesiva. [0065] De preferência, a doença é selecionada a partir do grupo gue consiste em doenças hepáticas metabólicas, doença hepática gordurosa não alcoólica (NAFLD), esteatohepatite não alcoólica (NASH), doenças hepáticas induzidas por drogas, doenças hepáticas induzidas por álcool, doenças hepáticas induzidas por agente infeccioso, doenças hepáticas inflamatórias, doenças hepáticas mediadas por disfunção do sistema imunológico, dislipidemia, doenças cardiovasculares, restenose, síndrome X, síndrome metabólica, diabetes, obesidade, hipertensão, colangiopatias crônicas como Colangite Esclerosante Primária (PSC), Colangite Biliar Primária (PBC), atresia biliar, colestase intra-hepática familiar tipo 3 (PFIC3), doenças inflamatórias intestinais, doença de Crohn, colite ulcerativa, câncer hepático, carcinoma hepatocelular, câncer gastrointestinal, câncer gástrico, câncer colorretal, fibrose ou cirrose hepática induzida por doença metabólica, fibrose ou cirrose induzida por NAFLD, fibrose ou cirrose induzida por NASH, fibrose ou cirrose hepática induzida por álcool, fibrose ou cirrose hepática induzida por drogas, fibrose ou cirrose hepática induzida por agente infeccioso, fibrose ou cirrose hepática induzida por infecção por parasita, fibrose ou cirrose hepática induzida por infecção bacteriana, fibrose ou cirrose induzida por35/70 arterial, venous fibrosis, ocular fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of pneumoconiosis in people who work with coal), proliferative fibrosis, neoplastic fibrosis, peri-implant fibrosis and asbestosis , arthrofibrosis, adhesive capsulitis. [0065] Preferably, the disease is selected from the group consisting of metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, diseases liver diseases induced by an infectious agent, inflammatory liver diseases, liver diseases mediated by immune system dysfunction, dyslipidemia, cardiovascular diseases, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC), Biliary Cholangitis Primary (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel disease, Crohn's disease, ulcerative colitis, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, colorectal cancer, fibrosis or induced liver cirrhosis due to metabolic disease, fibrosis or cirrhosis induced by NAFLD, fibrosis or cirrhosis NASH-induced ose, alcohol-induced fibrosis or liver cirrhosis, drug-induced fibrosis or liver cirrhosis, infectious agent-induced fibrosis or liver cirrhosis, parasitic infection-induced fibrosis or liver cirrhosis induced by bacterial infection, fibrosis or cirrhosis induced by
Petição 870190071527, de 26/07/2019, pág. 50/109Petition 870190071527, of 7/26/2019, p. 50/109
36/7036/70
infecção dupla por HCV e HIV, fibrose ou cirrose induzida por radiação ou quimioterapia, fibrose do trato biliar, fibrose ou cirrose hepática devido a qualquer doença colestática crônica, fibrose intestinal de qualquer etiologia, fibrose induzida por doença de Crohn, fibrose induzida por colite ulcerativa, fibrose do intestino (por exemplo, intestino delgado), fibrose de cólon, fibrose de estômago, fibrose pulmonar, fibrose consecutiva a doenças inflamatórias crônicas das vias aéreas, como COPD, asma, enfisema, pulmão de fumante, tuberculose, fibrose pulmonar, fibrose pulmonar idiopática (IPF).double infection with HCV and HIV, fibrosis or cirrhosis induced by radiation or chemotherapy, fibrosis of the biliary tract, fibrosis or liver cirrhosis due to any chronic cholestatic disease, intestinal fibrosis of any etiology, fibrosis induced by Crohn's disease, fibrosis induced by ulcerative colitis , fibrosis of the intestine (e.g. small intestine), colon fibrosis, stomach fibrosis, pulmonary fibrosis, fibrosis following chronic inflammatory airway diseases, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, fibrosis idiopathic pulmonary disease (IPF).
[0066] 0 termo tratamento ou tratar se refere à cura ou prevenção de um transtorno fibrótico em um indivíduo em necessidade do mesmo. 0 tratamento envolve a administração da combinação da invenção a um indivíduo que tem um transtorno declarado, isto é, a um paciente, para prevenir, curar, atrasar, reverter ou desacelerar a progressão do transtorno, melhorando, por meio disso, a condição do indivíduo. Um tratamento também pode ser administrado a um indivíduo gue é saudável ou está em risco de desenvolver um transtorno fibrótico.[0066] The term treatment or treat refers to the cure or prevention of a fibrotic disorder in an individual in need of it. The treatment involves administering the combination of the invention to an individual who has a reported disorder, i.e., a patient, to prevent, cure, delay, reverse or slow down the progression of the disorder, thereby improving the condition of the individual . A treatment can also be given to an individual who is healthy or at risk of developing a fibrotic disorder.
[0067] Portanto, de acordo com a invenção, o tratamento de uma doença imune, inflamatória, metabólica, fibrótica e colestática envolve a administração da combinação da presente invenção, por exemplo, na forma de uma composição farmacêutica contendo os componentes (i) e (ii) da[0067] Therefore, according to the invention, the treatment of an immune, inflammatory, metabolic, fibrotic and cholestatic disease involves the administration of the combination of the present invention, for example, in the form of a pharmaceutical composition containing the components (i) and (ii) from
Petição 870190071527, de 26/07/2019, pág. 51/109Petition 870190071527, of 7/26/2019, p. 51/109
37/70 combinação, a um indivíduo que tem um transtorno declarado para curar, atrasar, reverter ou desacelerar a progressão do transtorno, melhorando, dessa forma, a condição do paciente ou a um indivíduo saudável, em particular, a um indivíduo gue está em risco de desenvolver tal doença.37/70 combination, to an individual who has a disorder declared to cure, delay, reverse or slow the progression of the disorder, thereby improving the condition of the patient or a healthy individual, in particular, an individual who is in risk of developing such a disease.
[0068] 0 tratamento envolve a administração da combinação da invenção a um paciente que tem um transtorno declarado para curar, atrasar ou desacelerar o progresso, melhorando, dessa forma, a condição do paciente ou a um indivíduo saudável, em particular, um indivíduo que está em risco de desenvolver uma doença inflamatória, metabólica, fibrótica e colestática.[0068] The treatment involves administering the combination of the invention to a patient who has a declared disorder to cure, delay or slow down progress, thereby improving the condition of the patient or to a healthy individual, in particular, an individual who you are at risk of developing an inflammatory, metabolic, fibrotic and cholestatic disease.
[0069] 0 indivíduo a ser tratado é um mamífero, preferencialmente, um humano. 0 indivíduo a ser tratado de acordo com a invenção pode ser selecionado com base em diversos critérios associados a doenças fibróticas como tratamentos com fármaco anteriores, patologias associadas, genótipo, exposição a fatores de risco, infecção viral, assim como com base na detecção de qualquer biomarcador relevante que pode ser avaliado por meio de métodos de imageamento e métodos de detecção imunológica, bioquímica, enzimática, química ou de ácido nucleico.[0069] The individual to be treated is a mammal, preferably a human. The individual to be treated according to the invention can be selected based on several criteria associated with fibrotic diseases such as previous drug treatments, associated pathologies, genotype, exposure to risk factors, viral infection, as well as based on the detection of any relevant biomarker that can be assessed using imaging methods and methods of immunological, biochemical, enzymatic, chemical or nucleic acid detection.
[0070] Os indivíduos a serem tratados de acordo com a invenção podem ser selecionados com base em diversos critérios associados a doenças inflamatórias, metabólicas, fibróticas e colestáticas como tratamentos com fármaco anteriores, patologias associadas, genótipo, exposição a fatores de risco, infecção viral, assim como com base na detecção de qualquer biomarcador relevante que pode ser avaliado por meio de métodos de imageamento e métodos de[0070] The individuals to be treated according to the invention can be selected based on several criteria associated with inflammatory, metabolic, fibrotic and cholestatic diseases such as previous drug treatments, associated pathologies, genotype, exposure to risk factors, viral infection , as well as based on the detection of any relevant biomarker that can be evaluated by means of imaging methods and
Petição 870190071527, de 26/07/2019, pág. 52/109Petition 870190071527, of 7/26/2019, p. 52/109
38/70 detecção imunológica, bioquímica, enzimática, química ou de ácido nucleico.38/70 immunological, biochemical, enzymatic, chemical or nucleic acid detection.
[0071] A síntese de NTZ ou análogos pode ser, por exemplo, executada como descrito em (Rossignol e Cavier, 1975) , ou por qualquer outra via de síntese conhecida por um elemento versado na técnica.[0071] The synthesis of NTZ or analogues can, for example, be performed as described in (Rossignol and Cavier, 1975), or by any other route of synthesis known to an element skilled in the art.
[0072] Em uma modalidade particular, o tratamento de uma doença inflamatória, metabólica, fibrótica e colestática pode compreender a administração de uma composição que compreende pelo menos dois compostos selecionados a partir de NTZ e análogos de NTZ. Nessa modalidade, a administração de pelo menos um agonista de PPAR é fornecida na mesma composição que os dois compostos, ou em uma forma separada, como em uma composição diferente.[0072] In a particular embodiment, the treatment of an inflammatory, metabolic, fibrotic and cholestatic disease may comprise the administration of a composition comprising at least two compounds selected from NTZ and NTZ analogs. In this embodiment, the administration of at least one PPAR agonist is provided in the same composition as the two compounds, or in a separate form, as in a different composition.
[0073] Em uma outra modalidade, a combinação da invenção é para administração simultânea, sequencial ou separada em terapia, portanto, sendo possivelmente incluída em diferentes composições. No caso de administração sequencial, NTZ e/ou análogo (ou análogos) de NTZ pode ser administrada antes do agonista (ou agonistas) de PPAR, ou o agonista (ou agonistas) de PPAR é (são) administrado antes de NTZ e/ou análogo (ou análogos) de NTZ.[0073] In another embodiment, the combination of the invention is for simultaneous, sequential or separate administration in therapy, therefore, possibly being included in different compositions. In the case of sequential administration, NTZ and / or analogue (or analogues) of NTZ can be administered before the PPAR agonist (or agonists), or the PPAR agonist (or agonists) is (are) administered before NTZ and / or analog (or analogues) of NTZ.
[0074] NTZ e análogo de NTZ (ou análogos) podem ser formulados como sais farmaceuticamente aceitáveis, particularmente, sais de ácido ou base compatíveis com uso farmacêutico. Os sais de NTZ e análogo de NTZ (ou análogos) incluem sais de adição de ácido farmaceuticamente aceitáveis, sais de adição de base farmaceuticamente aceitáveis, sais metálicos farmaceuticamente aceitáveis, sais de amônio e amônio alquilado. Esses sais podem ser[0074] NTZ and NTZ analog (or analogues) can be formulated as pharmaceutically acceptable salts, particularly, acid or base salts compatible with pharmaceutical use. The NTZ and NTZ analogue salts (or the like) include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium. These salts can be
Petição 870190071527, de 26/07/2019, pág. 53/109Petition 870190071527, of 7/26/2019, p. 53/109
39/70 obtidos durante a etapa de purificação final do composto ou pela incorporação do sal no composto anteriormente purificado.39/70 obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound.
[0075] A combinação de um composto da Fórmula (I) ou (II) com um ou mais agonista (ou agonistas) de PPAR pode ser formulada como sais não tóxicos farmaceuticamente aceitáveis obtidos a partir de bases ou ácidos orgânicos ou inorgânicos do composto da Fórmula (I) ou (II) ou agonista (ou agonistas) de PPAR. Esses sais podem ser obtidos durante a etapa de purificação final do composto ou pela incorporação do sal no composto anteriormente purificado.[0075] The combination of a compound of Formula (I) or (II) with one or more agonists (or agonists) of PPAR can be formulated as non-toxic pharmaceutically acceptable salts obtained from bases or organic or inorganic acids of the compound of Formula (I) or (II) or agonist (or agonists) of PPAR. These salts can be obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound.
[0076] As composições farmacêuticas da presente invenção que compreendem um composto da Fórmula (I) ou (II) e um ou mais agonista (ou agonistas) de PPAR também podem compreender um ou diversos excipientes ou veículos, aceitáveis dentro de um contexto farmacêutico (por exemplo, soluções salinas, soluções fisiológicas, soluções isotônicas, etc., compatíveis com uso farmacêutico e bem conhecidas por um elemento de conhecimento comum na técnica).[0076] The pharmaceutical compositions of the present invention that comprise a compound of Formula (I) or (II) and one or more PPAR agonist (or agonists) may also comprise one or more excipients or vehicles, acceptable within a pharmaceutical context ( for example, saline solutions, saline solutions, isotonic solutions, etc., compatible with pharmaceutical use and well known for an element of common knowledge in the art).
[0077] Es sas composições também podem compreender um ou diversos agentes ou veículos escolhidos dentre dispersantes, solubilizantes, estabilizantes, conservantes, etc. Os agentes ou veículos úteis para essas formulações (líquidas e/ou injetáveis e/ou sólidas) são particularmente metilcelulose, hidroximetilcelulose, carboximetilcelulose, polissorbato 80, manitol, gelatina, lactose, óleos vegetais, acácia, lipossomas, etc.[0077] These compositions may also comprise one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc. The agents or vehicles useful for these formulations (liquid and / or injectable and / or solid) are particularly methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc.
[0078] Es sas composições podem ser formuladas na forma de suspensões injetáveis, géis, óleos, pomadas, pílulas,[0078] These compositions can be formulated in the form of injectable suspensions, gels, oils, ointments, pills,
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40/70 supositórios, pós, capas de gel, cápsulas, aerossóis, etc., eventualmente por meio de formas galênicas ou dispositivos que asseguram uma liberação prolongada e/ou lenta. Para esse tipo de formulação, agentes como celulose, carbonates ou amidos podem ser vantajosamente usados.40/70 suppositories, powders, gel caps, capsules, aerosols, etc., possibly through galenic forms or devices that ensure a prolonged and / or slow release. For this type of formulation, agents such as cellulose, carbonates or starches can be advantageously used.
[0079] As composições farmacêuticas da presente invenção que compreendem um composto da Fórmula (I) ou (II) e um ou mais agonista (ou agonistas) de PPAR podem ser administradas por vias diferentes e em formas diferentes. Por exemplo, o composto (ou compostos) pode ser administrado através de uma via sistêmica, via oral, parenteralmente, por inalação, por spray nasal, por instilação nasal, ou por injeção, como, por exemplo, intravenosamente, por via intramuscular, por via subeutânea, por via transdérmica, por via tópica, por via intra-arterial, etc.[0079] The pharmaceutical compositions of the present invention comprising a compound of Formula (I) or (II) and one or more PPAR agonists (or agonists) can be administered by different routes and in different forms. For example, the compound (or compounds) can be administered via a systemic route, orally, parenterally, by inhalation, by nasal spray, by nasal instillation, or by injection, such as, for example, intravenously, intramuscularly, by subeutaneous, transdermally, topically, intraarterially, etc.
[0080] Obviamente, a via de administração será adaptada à forma de NTZ e/ou análogo de NTZ (ou análogos) em combinação com um ou mais agonista (ou agonistas) de PPAR de acordo com os procedimentos bem conhecidos pelos elementos versados na técnica.[0080] Obviously, the route of administration will be adapted to the form of NTZ and / or analogue of NTZ (or analogues) in combination with one or more agonists (or agonists) of PPAR according to procedures well known to the elements skilled in the art .
[0081] A NTZ e/ou análogo de NTZ (ou análogos) em combinação com um ou mais agonista (ou agonistas) de PPAR é administrada em uma quantidade terapeuticamente eficaz. No contexto da invenção, o termo quantidade efetiva se refere a uma quantidade do composto suficiente para produzir o resultado terapêutico desejado.[0081] NTZ and / or NTZ analog (or analogues) in combination with one or more PPAR agonists (or agonists) is administered in a therapeutically effective amount. In the context of the invention, the term effective amount refers to an amount of the compound sufficient to produce the desired therapeutic result.
[0082] A frequência e/ou dose relativa para a administração pode ser adaptada por um elemento de conhecimento comum na técnica, em função do paciente, da[0082] The frequency and / or relative dose for administration can be adapted by an element of common knowledge in the technique, depending on the patient, the
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41/70 patologia, da forma de administração, etc. Tipicamente, a combinação (como na forma de uma composição farmacêutica ou um kit de partes) da presente invenção pode ser administrada para o tratamento de uma doença fibrótica a uma dose para NTZ, ou um análogo de NTZ ou um agonista de PPAR, como um composto da Fórmula (I) ou (II) ou (III), compreendida entre 0,01 mg/dia a 4000 mg/dia, como de 50 mg/dia a 2000 mg/dia, e particularmente de 100 mg/dia a 1000 mg/dia.41/70 pathology, form of administration, etc. Typically, the combination (as in the form of a pharmaceutical composition or kit of parts) of the present invention can be administered for the treatment of a fibrotic disease at a dose for NTZ, or an NTZ analogue or a PPAR agonist, as a compound of Formula (I) or (II) or (III), comprised between 0.01 mg / day to 4000 mg / day, as from 50 mg / day to 2000 mg / day, and particularly from 100 mg / day to 1000 mg / day.
[0083] A dose do agonista (ou agonistas) de PPAR na dita combinação pode variar de acordo com o próprio agonista de PPAR. A dose é adaptada à eficiência do agonista de PPAR.[0083] The dose of the PPAR agonist (or agonists) in said combination may vary according to the PPAR agonist itself. The dose is adapted to the efficiency of the PPAR agonist.
[0084] Em uma modalidade preferencial da invenção, NTZ é usada em combinação com Elafibranor a uma dose compreendida entre 100 mg/dia e 1000 mg/dia (como 1000 mg/dia) (em particular, 20 mg/dia a 40 mg/dia) para NTZ e 80 a 120 mg/dia para Elafibranor.[0084] In a preferred embodiment of the invention, NTZ is used in combination with Elafibranor at a dose between 100 mg / day and 1000 mg / day (such as 1000 mg / day) (in particular, 20 mg / day at 40 mg / day) day) for NTZ and 80 to 120 mg / day for Elafibranor.
[0085] Em uma outra modalidade preferencial, os ingredientes ativos são administrados como uma ou mais composição (ou composições) farmacêutica na forma de uma pílula destinada a uma ingestão oral. A administração pode ser realizada diariamente ou até mesmo várias vezes ao dia, se necessário.[0085] In another preferred embodiment, the active ingredients are administered as one or more pharmaceutical composition (or compositions) in the form of a pill intended for oral intake. Administration can be performed daily or even several times a day, if necessary.
[0086] A invenção é adicionalmente descrita em referência aos seguintes exemplos não limitantes.[0086] The invention is further described with reference to the following non-limiting examples.
DESCRIÇÃO DAS FIGURAS E TABELASDESCRIPTION OF FIGURES AND TABLES
Figura 1: Efeito antifibrótico de Elafibranor e nitazoxanida em hHSC induzido por TGFpFigure 1: Antifibrotic effect of Elafibranor and nitazoxanide in hHSC induced by TGFp
[0087] HSC desprovidas de soro foram pré-incubadas por 1 hora com Elafibranor (A) ou nitazoxanida (B) , ou[0087] serum-free HSCs were pre-incubated for 1 hour with Elafibranor (A) or nitazoxanide (B), or
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Bezafibrato (C) antes da ativação com o TGFpl de citocina pró-fibrogênico (1 ng/ml). Após 48 horas de incubação, a expressão de g-SMA foi medida por ELISA. Os valores obtidos foram transformados em porcentagem de inibição pelo controle de TGFpl. Os dados são apresentados como média (triplicatas) ± desvio padrão (DP)] . O ajuste de curva e o cálculo de metade da concentração máxima inibitória (IC50) foram realizados com software XLFit 5.3.1.3.Bezafibrate (C) before activation with the pro-fibrogenic cytokine TGFpl (1 ng / ml). After 48 hours of incubation, g-SMA expression was measured by ELISA. The values obtained were transformed into a percentage of inhibition by the control of TGFpl. Data are presented as mean (triplicates) ± standard deviation (SD)]. The curve adjustment and the calculation of half of the maximum inhibitory concentration (IC50) were performed with XLFit 5.3.1.3 software.
Figura 2: Combinação de Elafibranor com nitazoxanida inibe sinergicamente g-SMA em hHSC induzida por TGFplFigure 2: Combination of Elafibranor with nitazoxanide synergistically inhibits g-SMA in TGFpl-induced hHSC
[0088] As combinações foram testadas em um formato de matriz de resposta de dose e analisadas de acordo com o modelo de aditivismo Excesso em relação a Bem-estar (EOB). Uma diluição em série de Elafibranor (fileira) e nitazoxanida (coluna) foi preparada, incluindo seus respectivos controles de DMSO. As misturas resultantes foram adicionados à HSC desprovida de soro, 1 hora antes da ativação com o TGFpl de citocina pró-fibrogênico (1 ng/ml). (A) Porcentagem de inibição de α-SMA pelo controle de TGFpl para todos os pares de combinação. Os dados são apresentados como média de quadruplicatas. (B) As pontuações de EOB foram calculadas como descrito em Materiais e Métodos. Qualquer par de compostos com valor de EOB positivo foi considerado sinérgico (colorido de verde claro a preto). A pontuação de EOB total incluindo todas as combinações foi também calculada. (C) Valores de dados derivados de uma par de combinação sinérgica foram plotados em uma representação em gráfico de barras. Os dados são apresentados como média (quadruplicatas) ± desvio padrão (DP) . O modelo de EOHSA foi usado como descrito na seção[0088] The combinations were tested in a dose response matrix format and analyzed according to the Excess additivism in relation to Wellbeing (EOB) model. A serial dilution of Elafibranor (row) and nitazoxanide (column) was prepared, including their respective DMSO controls. The resulting mixtures were added to the serum-free HSC 1 hour before activation with the pro-fibrogenic cytokine TGFpl (1 ng / ml). (A) Percentage of α-SMA inhibition by TGFpl control for all combination pairs. Data are presented as an average of quadruplicates. (B) EOB scores were calculated as described in Materials and Methods. Any pair of compounds with positive EOB value was considered synergistic (colored from light green to black). The total EOB score including all combinations was also calculated. (C) Data values derived from a synergistic combination pair were plotted in a bar graph representation. Data are presented as mean (quadruplicates) ± standard deviation (SD). The EOHSA model was used as described in the section
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Materiais e Métodos para confirmar a sinergia dos pares de combinação NTZ/ELA selecionados.Materials and Methods to confirm the synergy of the selected NTZ / ELA combination pairs.
Figura 3: Combinação de agonistas de PPAR com nitazoxanida inibe sinergicamente seu g-SMA em hHSC induzida por TGFpl [0089] As combinações foram testadas em um formato de matriz de resposta de dose e analisadas de acordo com o modelo de aditivismo Excesso em relação a Bem-estar (EOB). A diluição em série de Saroglitazar, Seladelpar e Lanifibranor e nitazoxanida foi preparada, incluindo seus respectivos controles de DMSO. As misturas resultantes foram adicionados à HSC desprovida de soro, 1 hora antes da ativação com o TGFpl de citocina pró-fibrogênico (1 ng/ml). A porcentagem de inibição de g-SMA pelo controle de TGFpl para todos os pares de combinação foi calculada. As pontuações de EOB foram calculadas como descrito em Materiais e Métodos. Qualquer par de compostos com valor de EOB positivo foi considerado sinérgico (colorido de verde claro a preto).Figure 3: Combination of PPAR agonists with nitazoxanide synergistically inhibits their g-SMA in TGFpl-induced hHSC [0089] The combinations were tested in a dose response matrix format and analyzed according to the Excess additivism model compared to Well-being (EOB). Serial dilution of Saroglitazar, Seladelpar and Lanifibranor and nitazoxanide was prepared, including their respective DMSO controls. The resulting mixtures were added to the serum-free HSC 1 hour before activation with pro-fibrogenic cytokine TGFpl (1 ng / ml). The percentage of g-SMA inhibition by TGFpl control for all combination pairs was calculated. EOB scores were calculated as described in Materials and Methods. Any pair of compounds with a positive EOB value was considered synergistic (colored from light green to black).
[0090] A porcentagem de inibição de g-SMA pelo controle de TGFpl derivado de um par de combinação sinérgico foi plotada em uma representação de gráfico em barras. Os dados são apresentados como média (quadruplicatas) ± desvio padrão (DP) . 0 modelo de EOHSA foi usado como descrito na seção Materiais e Métodos para confirmar a sinergia dos pares de combinação.[0090] The percentage of inhibition of g-SMA by the control of TGFpl derived from a synergistic combination pair was plotted on a bar graph representation. Data are presented as mean (quadruplicates) ± standard deviation (SD). The EOHSA model was used as described in the Materials and Methods section to confirm the synergy of the combination pairs.
Figura 4: Teor de colágeno hepáticoFigure 4: Liver collagen content
[0091] Camundongos C57BL/6 de 6 semanas de idade foram[0091] 6 week old C57BL / 6 mice were
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44/70 alimentados com uma dieta de controle (CSAA), dieta CDAA + 1 % de CHOL (CDAAc) ou dieta CDAAc suplementada com NTZ (30 mg/kg/dia ou 100 mg/kg/dia por 12 semanas) ou Elafibranor (1 mg/kg/dia ou 3 mg/kg/dia) ou uma combinação de Elafibranor e NTZ (respectivamente, 1+30 mg/kg/dia, 1 +100 mg/kg/dia, 3+30 mg/kg/dia e 3 + 100 mg/kg/dia). Para cada gráfico, a quantidade exata de doses de exposição foi indicada.44/70 fed a control diet (CSAA), CDAA diet + 1% CHOL (CDAAc) or CDAAc diet supplemented with NTZ (30 mg / kg / day or 100 mg / kg / day for 12 weeks) or Elafibranor ( 1 mg / kg / day or 3 mg / kg / day) or a combination of Elafibranor and NTZ (respectively, 1 + 30 mg / kg / day, 1 + 100 mg / kg / day, 3 + 30 mg / kg / day and 3 + 100 mg / kg / day). For each graph, the exact number of exposure doses was indicated.
[0092] Após o sacrifício, o teor de colágeno hepático foi determinado.[0092] After sacrifice, the liver collagen content was determined.
Figura 5: Porcentagem de fibrose hepáticaFigure 5: Percentage of liver fibrosis
[0093] Camundongos C57BL/6 de 6 semanas de idade foram alimentados com uma dieta de controle (CSAA), dieta CDAA + 1 % de CHOL (CDAAc) ou dieta CDAAc suplementada com NTZ (30 mg/kg/dia ou 100 mg/kg/dia por 12 semanas) ou Elafibranor (1 mg/kg/dia ou 3 mg/kg/dia) ou uma combinação de Elafibranor e NTZ (respectivamente, 1+30 mg/kg/dia, 1 +100 mg/kg/dia, 3+30 mg/kg/dia e 3 + 100 mg/kg/dia). Para cada gráfico, a quantidade exata de doses de exposição foi indicada.[0093] 6 week old C57BL / 6 mice were fed a control diet (CSAA), CDAA diet + 1% CHOL (CDAAc) or CDAAc diet supplemented with NTZ (30 mg / kg / day or 100 mg / day) kg / day for 12 weeks) or Elafibranor (1 mg / kg / day or 3 mg / kg / day) or a combination of Elafibranor and NTZ (respectively 1 + 30 mg / kg / day, 1 + 100 mg / kg / day, 3 + 30 mg / kg / day and 3 + 100 mg / kg / day). For each graph, the exact number of exposure doses was indicated.
[0094] Após o sacrifício, a área de fibrose hepática foi determinado.[0094] After sacrifice, the area of liver fibrosis was determined.
Abreviaturas usadas nas figuras, nas tabelas e no texto:Abbreviations used in figures, tables and text:
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TIMPTIMP
TLR-4 inibidor de tecido de me taloproteaseTLR-4 metalloprotease tissue inhibitor
Receptor 4 Similar a TollReceiver 4 Similar to Toll
TZTZ
TizoxanidaTizoxanide
TZGTZG
VAP-1VAP-1
Glucuronideo de tizoxanida proteína 1 de adesão vascularVascular adhesion protein 1 tizoxanide glucuronide
EXEMPLOSEXAMPLES
MATERIAIS E MÉTODOSMATERIALS AND METHODS
[0095] Os compostos foram dissolvidos em sulfóxido de dimetila (DMSO, Fluka n° de catálogo 41640). Nitazoxanida (INTERCHIM n° de catálogo RQ550U), tizoxanida (INTERCHIM n° de catálogo RP253), Lanifibranor (ARK PHARM n° de catálogo AK689102), Seladelpar (ARK PHARM n° de catálogo AK689146) e Saroglitazar (CHEMEXPRESS n° de catálogo YY-1997A) foram obtidos comercialmente.[0095] The compounds were dissolved in dimethyl sulfoxide (DMSO, Fluka catalog number 41640). Nitazoxanide (INTERCHIM catalog number RQ550U), tizoxanide (INTERCHIM catalog number RP253), Lanifibranor (ARK PHARM catalog number AK689102), Seladelpar (ARK PHARM catalog number AK689146) and Saroglitazar (CHEMEXPRESS catalog number YY -1997A) were obtained commercially.
Cultura de hHSCHHSC Culture
[0096] As células estreladas hepáticas primárias humanas (hHSC) (Innoprot) foram cultivadas em meio STeCM (ScienCell n° de catálogo 5301) que foi suplementado com 2 % de soro bovino fetal (FBS, ScienCell n° de catálogo 0010), 1 % de penicilina / estreptomicina (ScienCell n° de catálogo 0503) e suplemento de crescimento de célula estrelada (SteCGS; ScienCell n° de catálogo 5352). Os frascos de cultura celular foram revestidos com Poli-L lisina (Sigma n° de catálogo P4707) para uma melhor aderência.[0096] Human primary hepatic stellate cells (hHSC) (Innoprot) were cultured in STeCM medium (ScienCell catalog number 5301) which was supplemented with 2% fetal bovine serum (FBS, ScienCell catalog number 0010), 1 % penicillin / streptomycin (ScienCell catalog number 0503) and stellate cell growth supplement (SteCGS; ScienCell catalog number 5352). Cell culture flasks were coated with Poly-L lysine (Sigma catalog number P4707) for better adherence.
Preparação de composiçõesPreparation of compositions
Matriz de combinação de 2 componentes (NTZ/Elafibranor)2-component combination matrix (NTZ / Elafibranor)
[0097] Para esses experimentos, uma matriz de tabuleiro de xadrez foi gerada. Os estoques de NTZ e Elafibranor foram serialmente diluídos em DMSO em séries de 5 pontos em uma fileira (agonista de PPAR Elafibranor) e uma séries de[0097] For these experiments, a chessboard matrix was generated. NTZ and Elafibranor stocks were serially diluted in DMSO in series of 5 points in a row (PPAR agonist Elafibranor) and a series of
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48/70 pontos em uma coluna NTZ) de uma placa de 96 poços ou uma placa de 384 poços. Subsequentemente, a matriz de combinação 5X6 foi gerada pela mistura 1:1 de todas as concentrações de agente individuais. As concentrações de teste para cada composto foram escolhidas com base na respectiva IC50 de cada composto como agente individual obtida pela medição de teor de α-SMA no modelo de HSC estimulado com TGF-βΙ.48/70 points in an NTZ column) from a 96-well plate or a 384-well plate. Subsequently, the 5X6 combination matrix was generated by mixing 1: 1 of all concentrations of individual agent. The test concentrations for each compound were chosen based on the respective IC50 of each compound as an individual agent obtained by measuring the content of α-SMA in the HSC model stimulated with TGF-βΙ.
[0098] Então, concentrações 2 vezes e 4 vezes mais altas e mais baixas foram selecionadas.[0098] So, concentrations 2 times and 4 times higher and lower were selected.
Ativação de hHSC com TGF-βΙ e tratamento com compostoActivation of hHSC with TGF-βΙ and treatment with compound
[0099] As células estreladas hepáticas primárias humanas (hHSC) (Innoprot) foram cultivada sob condições padrão, como descrito acima. As células foram subsequentemente plaqueadas a uma densidade de 2 x 104 células/poço em placas de 96 poços e 6500 células/poço em placas de 384 poços para a medição de α-SMA por ELISA. No dia seguinte, o meio de cultura celular foi removido, e as células foram lavadas com Solução Salina Tamponada com Fosfato (PBS) (Invitrogen n° de catálogo 14190) . As hHSC foram desprovidas por 24 horas em meio livre de soro e livre de SteCGS.[0099] Human primary liver stellate cells (hHSC) (Innoprot) were cultured under standard conditions, as described above. The cells were subsequently plated at a density of 2 x 10 4 cells / well in 96-well plates and 6500 cells / well in 384-well plates for the measurement of α-SMA by ELISA. The next day, the cell culture medium was removed, and the cells were washed with Phosphate Buffered Saline (PBS) (Invitrogen catalog number 14190). The hHSC were deprived for 24 hours in serum-free and SteCGS-free media.
[0100] Para os tratamentos com NTZ, Elafibranor ou outros agonistas de PPAR e as respectivas combinações de NTZ/Elafibranor ou agonistas de PPAR, as hHSC desprovidas de soro foram pré-incubadas por 1 hora com os compostos seguido pela adição de TGF-βΙ de estímulos pró-fibrogênicos (PeproTech n° de catálogo 100-21, 1 ng/ml) em meio livre de soro e livre de SteCGS por um período adicional de 48 horas.[0100] For treatments with NTZ, Elafibranor or other PPAR agonists and the respective combinations of NTZ / Elafibranor or PPAR agonists, serum-free hHSCs were pre-incubated for 1 hour with the compounds followed by the addition of TGF-βΙ of pro-fibrogenic stimuli (PeproTech catalog number 100-21, 1 ng / ml) in serum-free and SteCGS-free medium for an additional 48 hours.
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ELISA de g-SMAG-SMA ELISA
[0101] 0 nivel de α-SMA foi medido usando um ELISA Sandwich. Em suma, os poços de uma placa de ELISA foram primeiramente revestidos com o anticorpo de captura (antiACTA2 monoclonal de camundongo, Abnova) a 4 °C durante a noite. Após 3 lavagens em PBS + 0,2 % de Tween 20, uma solução de bloqueio consistindo em PBS +0,2 % de BSA foi adicionada por uma hora seguido por um outro ciclo de lavagem. Os lisatos celulares foram transferidos para os poços para ligação ao anticorpo de captura por um periodo de 2h à temperatura ambiente. Após o procedimento de lavagem, o anticorpo de detecção (anti-ACTA2 monoclonal de camundongo biotinilado, Abnova) foi adicionado por 2 horas à temperatura ambiente seguido de 3 lavagens. Para a detecção, um Estreptavidina conjugada com HRP (R&D Systems n° de catálogo DY998) foi primeiramente aplicada por 30 min à temperatura ambiente. Após a lavagem, o substrato de HRP TMB (BD, n° 555214) foi adicionado e incubado por 7 min à temperatura ambiente no escuro. Mediante a oxidação, TMB forma um produto de reação azul solúvel em água que se torna amarelo com adição de ácido sulfúrico (parada de solução), permitindo a medição precisa da intensidade a 450 nm usando um espectrofotômetro. A color desenvolvida é diretamente proporcional à quantidade de α-SMA presente no lisato.[0101] The level of α-SMA was measured using a Sandwich ELISA. In short, the wells of an ELISA plate were first coated with the capture antibody (mouse monoclonal anti-ACTA2, Abnova) at 4 ° C overnight. After 3 washes in PBS + 0.2% Tween 20, a blocking solution consisting of PBS +0.2% BSA was added for one hour followed by another wash cycle. The cell lysates were transferred to the wells for binding to the capture antibody for a period of 2 hours at room temperature. After the washing procedure, the detection antibody (biotinylated mouse monoclonal anti-ACTA2, Abnova) was added for 2 hours at room temperature followed by 3 washes. For detection, a Streptavidin conjugated to HRP (R&D Systems catalog number DY998) was first applied for 30 min at room temperature. After washing, the HRP TMB substrate (BD, No. 555214) was added and incubated for 7 min at room temperature in the dark. Upon oxidation, TMB forms a blue water-soluble reaction product that turns yellow with the addition of sulfuric acid (solution stop), allowing precise measurement of intensity at 450 nm using a spectrophotometer. The color developed is directly proportional to the amount of α-SMA present in the lysate.
Determinação de sinergia por método de Excesso em relação a Bem-estar (EOB) e confirmação por EOSHA (Excesso em relação a Agente Individual Mais Alto)Synergy determination by method of Excess in relation to Well-Being (EOB) and confirmation by EOSHA (Excess in relation to Higher Individual Agent)
[0102] Os valores obtidos nos ensaios ELISA de «SMA foram primeiramente transformados em porcentagem de[0102] The values obtained in the «SMA ELISA assays were first transformed into a percentage of
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50/70 inibições pelo controle de TGF-βΙ. Então, com o uso dessa porcentagem de inibições, o EOB (Excesso em relação a Bemestar) foi determinado para definir os efeitos sinérgicos de combinações de fármacos. A pontuação de aditivismo de Bem-estar Esperado (E) foi primeiramente determinada pela equação:50/70 inhibitions by TGF-βΙ control. Then, using this percentage of inhibitions, the EOB (Excess in relation to Bemestar) was determined to define the synergistic effects of drug combinations. The expected Wellbeing additivism score (E) was first determined by the equation:
[0103] E = (A + B) - (A x B) em que A e B são a porcentagem de inibição de NTZ (A) e Elafibranor, Saroglitazar, Seladelpar ou Lanifibranor (B) a uma determinada dose. A diferença entre a expectativa de Bemestar e a inibição observada de NTZ/Elafibranor, Saroglitazar, Seladelpar ou Lanifibranor combinados na mesma dose é a pontuação de Excesso em relação a Bemestar .[0103] E = (A + B) - (A x B) where A and B are the percentage of inhibition of NTZ (A) and Elafibranor, Saroglitazar, Seladelpar or Lanifibranor (B) at a given dose. The difference between the expectation of Bemestar and the observed inhibition of NTZ / Elafibranor, Saroglitazar, Seladelpar or Lanifibranor combined in the same dose is the Excess score in relation to Bemestar.
- Pontuação de Excesso em relação a Bem-estar = 0 indica que o tratamento de combinação é aditivo (como esperado para efeitos de via independentes);- Excess score in relation to Well-being = 0 indicates that the combination treatment is additive (as expected for the purposes of independent pathways);
- Pontuação de Excesso em relação a Bem-estar >0 indica atividade maior que aditiva (sinergia); e- Excess score in relation to well-being> 0 indicates greater than additive activity (synergy); and
- Pontuação de Excesso em relação a Bem-estar <0 indica que a combinação é menos que aditiva (antagonismo). Para a combinação NTZ + Elafibranor, uma pontuação de Bem-estar total adicional foi calculada pela soma de todo EOB.- Excess score in relation to Wellbeing <0 indicates that the combination is less than additive (antagonism). For the NTZ + Elafibranor combination, an additional total Wellness score was calculated by adding the entire EOB.
[0104] EOHSA é uma medida padrão de sinergia usada pela FDA para avaliação de combinações de fármacos e é calculada como a diferença do efeito produzido pela combinação de fármacos e o maior efeito produzido por cada um dos agentes individuais da combinação nas mesmas concentrações como quando combinados (Borisy et al. , 2003) . Para combinações sinérgicas identificadas pelo método de EOB, o % de[0104] EOHSA is a standard measure of synergy used by the FDA to evaluate drug combinations and is calculated as the difference in effect produced by the drug combination and the greatest effect produced by each of the individual agents in the combination at the same concentrations as when combined (Borisy et al., 2003). For synergistic combinations identified by the EOB method, the% of
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51/70 inibição experimental foi plotado em um gráfico de barras e a significância das diferenças observadas entre NTZ/ELA e o agente individual foi estimada por ANOVA de um fator e LSD da Fisher não corrigido post-hoc (*: p<0,05; **: p<0,01; ***: p<0,001).51/70 experimental inhibition was plotted on a bar graph and the significance of the differences observed between NTZ / ALS and the individual agent was estimated by one-way ANOVA and Fisher's LSD uncorrected post-hoc (*: p <0.05 ; **: p <0.01; ***: p <0.001).
Avaliação de Elafibranor. Nitazoxanida e a combinação Elafibranor + nitazoxanida em um modelo de CDAA + 1 % de colesterol crônico se NASH fibrosante (12 semanas) Projeto experimentalEvaluation of Elafibranor. Nitazoxanide and the combination Elafibranor + nitazoxanide in a model of CDAA + 1% chronic cholesterol if fibrous NASH (12 weeks) Experimental project
[0105] A dieta definida de L-aminoácido e deficiente de colina (CDAA) carece de colina, que é essencial para βoxidação hepática e produção de lipoproteína de densidade muito baixa, e acredita-se que induza os hepatócitos a armazenar gordura e, subsequentemente, provocar danificação celular. 0 modelo de roedor induzido por dieta CDAA desenvolve fibrose dentro de um período de tempo relativamente curto, ideal para estudar rapidamente a capacidade de reversão de patologia NASH, particularmente fibrose.[0105] The defined choline-deficient L-amino acid (CDAA) diet lacks choline, which is essential for hepatic βoxidation and very low density lipoprotein production, and is believed to induce hepatocytes to store fat and subsequently , cause cell damage. The CDAA diet-induced rodent model develops fibrosis within a relatively short period of time, ideal for quickly studying the ability to reverse NASH pathology, particularly fibrosis.
[0106] A ingestão de colesterol aumentada acelera a fibrose hepática em diversos modelos de camundongo de NASH. A exacerbação de fibrose hepática envolve principalmente o acúmulo de colesterol livre em células estreladas hepáticas, que sensibiliza as células para fator β de crescimento de transformação (ΤΟΕβ) e, subsequentemente, agrava a fibrose hepática.[0106] Increased cholesterol intake accelerates liver fibrosis in several NASH mouse models. The exacerbation of hepatic fibrosis mainly involves the accumulation of free cholesterol in hepatic stellate cells, which sensitizes cells to transforming growth factor β (ΤΟΕβ) and subsequently worsens liver fibrosis.
[0107] No presente estudo, foram examinados os efeitos de nitazoxanida em fibrose hepática em camundongos C57BI/6J alimentados com uma dieta CDAA suplementada com 1 % de colesterol.[0107] In the present study, the effects of nitazoxanide on liver fibrosis in C57BI / 6J mice fed a CDAA diet supplemented with 1% cholesterol were examined.
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52/7052/70
[0108] Os efeitos preventivos de Elafibranor sozinho, NTZ sozinha e a combinação de ambos foram avaliados em um modelo de camundongos de NASH fibrosante alimentados com uma dieta CDAA + 1 % de colesterol. Os camundongos machos C57BI/6J com 6 semanas de idade foram alimentados com uma dieta de controle (CSAA), dieta CDAA + 1 % de colesterol ou dieta CDAA + 1 % de colesterol suplementada com Elafibranor[0108] The preventive effects of Elafibranor alone, NTZ alone and the combination of both were evaluated in a model of fibrous NASH mice fed a CDAA + 1% cholesterol diet. The 6 week old male C57BI / 6J mice were fed a control diet (CSAA), CDAA + 1% cholesterol diet or CDAA + 1% cholesterol diet supplemented with Elafibranor
monitorados duas vezes por semana. No último dia de tratamento, os camundongos foram sacrificados após um periodo de jejum de 6 h. O fígado foi rapidamente excisado para estudos bioquímicos e histológicos.monitored twice a week. On the last day of treatment, the mice were sacrificed after a 6 h fasting period. The liver was quickly excised for biochemical and histological studies.
[0110] Todos os procedimentos com animal foram realizados de acordo com os protocolos padrão e de acordo com as recomendações padrão para o cuidado apropriado e o uso de animais de laboratório.[0110] All animal procedures were performed in accordance with standard protocols and in accordance with standard recommendations for the appropriate care and use of laboratory animals.
[0111] Os camundongos machos C57BL/6 com 6 semanas de idade foram alimentados por 12 semanas de acordo com um plano experimental detalhado na tabela 1:[0111] 6 week old male C57BL / 6 mice were fed for 12 weeks according to an experimental plan detailed in table 1:
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53/7053/70
[0112] O controle foi a dieta CSAA.[0112] The control was the CSAA diet.
[0113] Alguns camundongos foram alimentados com a dieta CDAAc.[0113] Some mice were fed the CDAAc diet.
[0114] Alguns camundongos foram alimentados com dieta CDAAc suplementada com Elafibranor a 1 ou 3 mg/kg/dia. Alguns camundongos foram alimentados com dieta CDAAc suplementada com NTZ a 30 ou 100 mg/kg/dia.[0114] Some mice were fed a CDAAc diet supplemented with Elafibranor at 1 or 3 mg / kg / day. Some mice were fed a CDAAc diet supplemented with NTZ at 30 or 100 mg / kg / day.
[0115] Alguns camundongos foram alimentados com dieta[0115] Some mice were fed a diet
camundongos C57BI/6J alimentados com CDAA + nitazoxanida 0,02 % (p/p) correspondente à dose teórica de 30 mg/kg/dia. [0117] 0 grupo que corresponde à dieta CDAAc suplementada com NTZ a 100 mg/kg é também chamado de camundongos C57BI/6J alimentados com CDAA + nitazoxanida 0,0667 % (p/p) correspondente à dose teórica de 100 mg/kg/dia.C57BI / 6J mice fed with CDAA + 0.02% nitazoxanide (w / w) corresponding to the theoretical dose of 30 mg / kg / day. [0117] The group corresponding to the CDAAc diet supplemented with NTZ at 100 mg / kg is also called C57BI / 6J mice fed with CDAA + 0.0667% (w / w) nitazoxanide corresponding to the theoretical dose of 100 mg / kg / day.
[0118] 0 alimento foi adquirido junto à empresa Ssniff®[0118] The food was purchased from the company Ssniff®
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54/70 (Soest, Alemanha).54/70 (Soest, Germany).
[0119] Nit azoxanida (consultar referência na Tabela 1) foi incorporada pela Ssniff® em dieta CDAA + 1 % de col em forma de pó à dose requerida.[0119] Nit azoxanide (see reference in Table 1) was incorporated by Ssniff® in CDAA diet + 1% col in powder form at the required dose.
[0120] A referência e o número do lote de nitazoxanida são resumidos na Tabela 2:[0120] The reference and batch number of nitazoxanide are summarized in Table 2:
Tabela 2: Referências de nitazoxanidaTable 2: Nitazoxanide references
[0121] Para cada dose, um cálculo das doses exatas foi feito de acordo com o exemplo a seguir. Isso permite considerar a dose exata de cada produto que foi exatamente consumido por cada grupo de camundongos.[0121] For each dose, a calculation of the exact doses was made according to the following example. This allows us to consider the exact dose of each product that was exactly consumed by each group of mice.
Cálculo das doses de tratamento reais: exemplo com nitazoxanida a 0,02 % (peso/peso) • A ingestão de alimento é expressa em gramas de alimento / gramas de animal / dia • 0,02 % de nitazoxanida na dieta o 0,02 g de cpd /100 g de alimento=0,2 mg de cpd/g de alimento • Dose real de cpd:Calculation of actual treatment doses: example with 0.02% nitazoxanide (weight / weight) • Food intake is expressed in grams of food / grams of animal / day • 0.02% of nitazoxanide in the diet o 0.02 g cpd / 100 g of food = 0.2 mg cpd / g of food • Actual dose of cpd:
o 0,2 mg de cpd/grama de alimento/grama de animal/dia o (0,2 mg de cpd/grama de alimento/grama de animal/dia)X1000= (0,2 mg de cpd/grama de alimento/kg de animal/dia)=200 mg de cpd/grama de alimento/kg de animal por diao 0.2 mg cpd / gram of food / gram of animal / day o (0.2 mg cpd / gram of food / gram of animal / day) X1000 = (0.2 mg cpd / gram of food / kg of animal / day) = 200 mg cpd / gram of food / kg of animal per day
[0122] Consequentemente, a multiplicação por 200 do valor de ingestão de alimento expresso em gramas de[0122] Consequently, multiplying by 200 the amount of food intake expressed in grams of
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55/70 alimento / gramas de animal / dia; o valor obtido corresponde à dose administrada real expressa em mg de NTZ/kg de animal/dia.55/70 food / grams of animal / day; the value obtained corresponds to the actual administered dose expressed in mg of NTZ / kg of animal / day.
[0123] Da mesma maneira:[0123] In the same way:
• para a dose de NTZ 0,00667 % p/p, a dose de tratamento real foi obtida pela multiplicação do valor de ingestão de alimento (gramas de alimento / gramas de animal / dia) por 66,7.• for the NTZ dose 0.00667% w / w, the actual treatment dose was obtained by multiplying the value of food intake (grams of food / grams of animal / day) by 66.7.
• para a dose de NTZ 0, 0667 % p/p, a dose de tratamento real foi obtida pela multiplicação do valor de ingestão de alimento (gramas de alimento / gramas de animal / dia) por 667.• for the dose of NTZ 0, 0667% w / w, the actual treatment dose was obtained by multiplying the amount of food intake (grams of food / grams of animal / day) by 667.
[0124] De acordo com o cálculo, a dose calculada versus a dose estimada são dadas nas tabelas 3 e 4 a seguir.[0124] According to the calculation, the calculated dose versus the estimated dose are given in tables 3 and 4 below.
Tabela 3: Doses calculadas e estimadas para cada composto de uma dose diferenteTable 3: Calculated and estimated doses for each compound of a different dose
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56/70 em doses diferentes56/70 in different doses
[0125] 0 peso corporal e a ingestão de alimento foram registrados duas vezes na semana ao longo do estudo.[0125] Body weight and food intake were recorded twice a week throughout the study.
[0126] No fim do periodo de tratamento, os animais foram anestesiados com isoflurano e amostras sanguíneas foram tiradas como descrito abaixo. Os animais foram, então, sacrificados por deslocamento cervical e decapitados para excisão cerebral e pesagem. 0 fígado foi também coletado e pesado. Parte do fígado foi fixada em 4 % de formalina, embebida em parafina e usada para análises histológicas. 0 fígado remanescente foi congelado rapidamente em nitrogênio líquido e mantido a -80 °C até uso para análises adicionais.[0126] At the end of the treatment period, the animals were anesthetized with isoflurane and blood samples were taken as described below. The animals were then sacrificed by cervical dislocation and beheaded for brain excision and weighing. The liver was also collected and weighed. Part of the liver was fixed in 4% formalin, embedded in paraffin and used for histological analysis. The remaining liver was quickly frozen in liquid nitrogen and kept at -80 ° C until use for further analysis.
[0127] A amostragem sanguínea foi realizada no sacrifício após um período de jejum de 6 horas. As amostras sanguíneas foram retiradas sob anestesia por punção retroorbital. Tubos de heparina contendo sangue foram rapidamente centrifugados (15 minutos a 4.000 rpm/4 °C) e a fração de plasma foi coletada. Alíquotas de plasma foram armazenadas a -20 °C até análises adicionais.[0127] Blood sampling was performed at sacrifice after a 6-hour fasting period. Blood samples were taken under anesthesia by retroorbital puncture. Heparin tubes containing blood were rapidly centrifuged (15 minutes at 4,000 rpm / 4 ° C) and the plasma fraction was collected. Plasma aliquots were stored at -20 ° C until further analysis.
Bioquímica de plasmaPlasma biochemistry
Alanina Aminotransferase (ALT)Alanine Aminotransferase (ALT)
[0128] A concentração plasmática de ALT foi determinada usando o kit Randox apropriado para Daytona automate (Randox, n° de catálogo AL 3801) . Em suma, a ALT dentro da amostra de plasma transforma enzimaticamente a-oxoglutarato e L-alanina em L-glutamato e piruvato. Na presença de NADH, o piruvato gerado é convertido por lactato desidrogenase para formar L-lactato e NAD+. A cinética da reação é[0128] The plasma ALT concentration was determined using the appropriate Randox kit for Daytona automate (Randox, catalog number AL 3801). In short, ALT within the plasma sample enzymatically transforms a-oxoglutarate and L-alanine into L-glutamate and pyruvate. In the presence of NADH, the pyruvate generated is converted by lactate dehydrogenase to form L-lactate and NAD + . The reaction kinetics is
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57/70 estudada e permite que o nível plasmático de ALT seja calculado. Os resultados são expressos em U/l.57/70 studied and allows the plasma ALT level to be calculated. The results are expressed in U / l.
Aspartato Aminotransferase (AST)Aspartate Aminotransferase (AST)
[0129] A concentração plasmática de AST foi determinada usando o kit Randox apropriado para Daytona automate (Randox, n° de catálogo AS 3804) . Em suma, a AST dentro da amostra de plasma transforma enzimaticamente a-oxoglutarato e L-aspartato em L-glutamato e oxaloacetato. Na presença de NADH, o oxaloacetato gerado é convertido por malato desidrogenase para formar L-malato e NAD+. A cinética da reação é estudada e permite que os níveis plasmáticos de AST sejam calculados. Os resultados são expressos em U/l.[0129] The plasma AST concentration was determined using the appropriate Randox kit for Daytona automate (Randox, catalog number AS 3804). In short, AST within the plasma sample enzymatically transforms a-oxoglutarate and L-aspartate into L-glutamate and oxaloacetate. In the presence of NADH, the oxaloacetate generated is converted by malate dehydrogenase to form L-malate and NAD + . The kinetics of the reaction is studied and allows the plasma AST levels to be calculated. The results are expressed in U / l.
HistologiaHistology
[0130] No sacrifício, as amostras de fígado foram processadas para análise histológica e examinadas da seguinte forma.[0130] At sacrifice, liver samples were processed for histological analysis and examined as follows.
Embebição e secionamento de tecidoSoaking and sectioning tissue
[0131] As fatias de fígado foram primeiramente fixadas por 12 horas em solução de formalina a 4 %. Então, os pedaços de fígado foram lavados por 30 minutos em PBS, e desidratados em soluções de etanol (banhos sucessivos a 70, 80, 95 e 100 % de etanol) . Os pedaços de fígado foram incubados em três banhos diferentes de Xileno (SigmaAldrich n° de catálogo 534056), seguido de dois banhos em parafina líquida (60 °C). Os pedaços de fígado foram,[0131] The liver slices were first fixed for 12 hours in 4% formalin solution. Then, the liver pieces were washed for 30 minutes in PBS, and dehydrated in ethanol solutions (successive baths at 70, 80, 95 and 100% ethanol). The liver pieces were incubated in three different Xylene baths (SigmaAldrich catalog number 534056), followed by two baths in liquid paraffin (60 ° C). The liver pieces were,
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58/70 temperatura ambiente. Os blocos de fígado foram cortados em fatias de 3 pm.58/70 room temperature. The liver blocks were cut into 3 pm slices.
Coloração vermelho da SíriaSyrian red coloring
[0133] As seções de fígado foram desparafinizadas, rehidratadas e incubadas por 15 minutos em uma solução de Fast Green FCF 0,04 % (Sigma-Aldrich, n° de catálogo F7258) antes do enxágue em um banho de 0,5 % de ácido acético (Sigma-Aldrich, n° de catálogo 695092) . Então, as seções de fígado foram enxaguadas em água e incubadas 30 minutos em uma solução de Fast Green FCF 0,04 % - 0,1 % de vermelho da Síria (Vermelho Direto 80, Fluka n° de catálogo 43665) em ácido pícrico aquoso saturado (Sigma-Aldrich n° de catálogo P6744). As seções foram, então, desidratadas e montadas usando o meio GV Mount (Leica, n° de catálogo 14046430011) . Exames histológicos[0133] The liver sections were dewaxed, rehydrated and incubated for 15 minutes in a 0.04% Fast Green FCF solution (Sigma-Aldrich, catalog number F7258) before rinsing in a 0.5% acetic acid (Sigma-Aldrich, catalog number 695092). Then, the liver sections were rinsed in water and incubated for 30 minutes in a solution of Fast Green FCF 0.04% - 0.1% Syrian red (Direct Red 80, Fluka catalog number 43665) in aqueous picric acid saturated (Sigma-Aldrich catalog number P6744). The sections were then dehydrated and assembled using the GV Mount medium (Leica, catalog number 14046430011). Histological exams
[0134] Um técnico sem conhecimento da fonte de cada espécime de fígado realizou exames histológicos. Lâminas virtuais foram geradas usando o escâner Pannoramic 250 da 3D Histech. Com o uso do software Quant Center (3D Histech, incluindo os módulos Pattern Quant e Histo Quant), as áreas com cor de colágeno foram quantificadas. Em suma, Pattern Quant foi usado para detectar o tecido e medir sua superfície. Então, Histo Quant foi usado para detectar o teor de colágeno com coloração e medir sua superfície, com base em um método de limite de cor. A área de fibrose foi, então, expressa como a porcentagem da superfície de colágeno para todo o tecido para cada animal.[0134] A technician without knowledge of the source of each liver specimen performed histological examinations. Virtual slides were generated using the 3D Histech Pannoramic 250 scanner. Using the Quant Center software (3D Histech, including the Pattern Quant and Histo Quant modules), the areas with collagen color were quantified. In short, Pattern Quant was used to detect the fabric and measure its surface. Then, Histo Quant was used to detect the collagen content with color and measure its surface, based on a color limit method. The fibrosis area was then expressed as the percentage of the collagen surface for all tissue for each animal.
[0135] Os estágios de fibrose hepática foram avaliados às cegas, usando critérios de fibrose de CRN.[0135] The stages of liver fibrosis were assessed blindly, using CRN fibrosis criteria.
[0136] Os detalhes sobre os parâmetros,[0136] Details about the parameters,
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59/70 quantificação/contagem e número de campos considerados são fornecidos na tabela 5 a seguir.59/70 quantification / count and number of fields considered are provided in table 5 below.
Tabela 5: Critérios de CRN para fibroseTable 5: CRN criteria for fibrosis
Análise estatísticaStatistical analysis
[0137] Os resultados experimentais foram expressos como média ± desvio padrão (DP) e plotados como gráficos em barras ou curvas. As análises estatísticas foram realizadas usando Prism Versão 7, da seguinte forma:[0137] The experimental results were expressed as mean ± standard deviation (SD) and plotted as bar graphs or curves. Statistical analyzes were performed using Prism Version 7, as follows:
[0138] Para as medições realizadas após o sacrifício, grupos de CSAA vs CDAA + 1 % de col foram comparados por um teste t de Student (#: p<0,05; ##: p<0,01; ###: p<0,001) ou por um teste de Mann-Whitney ($: p<0,05; $$: p<0,01; $$$: p<0,001). Os grupos de tratamento foram comparados com dieta CDAA + 1 % de col por ANOVA de um fator e LSD de Fisher não corrigido post-hoc (*: p<0,05; **: p<0,01; ***:[0138] For measurements performed after sacrifice, groups of CSAA vs CDAA + 1% col were compared by Student's t test (#: p <0.05; ##: p <0.01; ### : p <0.001) or by a Mann-Whitney test ($: p <0.05; $$: p <0.01; $$$: p <0.001). The treatment groups were compared with CDAA diet + 1% col by one-way ANOVA and post-hoc uncorrected Fisher's LSD (*: p <0.05; **: p <0.01; ***:
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60/70 p<0,001).60/70 p <0.001).
Medição de teor de colágeno hepáticoMeasurement of hepatic collagen content
[0139] 0 teor de colágeno hepático foi determinado usando o kit QuickZyme apropriado (ensaio de colágeno total, n° de catálogo QZB-totcol5). O ensaio é baseado na detecção de hidroxiprolina, que é um aminoácido não proteinogênico principalmente encontrado na hélice tripla de colágeno. Assim, a hidroxiprolina em hidrolisatos de tecido pode ser usada como uma medição direta da quantidade de colágeno presente no tecido (sem discriminação entre pró-colágeno, colágeno maduro e produtos de degradação de colágeno).[0139] The liver collagen content was determined using the appropriate QuickZyme kit (total collagen assay, catalog number QZB-totcol5). The assay is based on the detection of hydroxyproline, which is a non-proteinogenic amino acid mainly found in the triple collagen helix. Thus, hydroxyproline in tissue hydrolysates can be used as a direct measurement of the amount of collagen present in the tissue (without discrimination between pro-collagen, mature collagen and collagen degradation products).
[0140] A hidrólise completa de amostras de tecido em 6M de HC1 a 95 °C é requerida antes da dosagem da hidroxiprolina. Os resultados do ensaio na geração de um cromógeno com uma absorbância máxima a 57 0 nm. Os resultados são expressos como mg de colágeno z g de fígado.[0140] Complete hydrolysis of tissue samples in 6M HCl at 95 ° C is required prior to hydroxyproline dosing. The test results in the generation of a chromogen with a maximum absorbance at 57 0 nm. The results are expressed as mg of collagen z g of liver.
Pró-peptideo de N-terminal de Pró-colágeno III (PIIINP)Pro-collagen III N-terminal peptide (PIIINP)
[0141] A concentração plasmática de PIIINP foi determinada usando um ensaio ELISA de Cloud-Clone Corp (n° de catálogo SEA573Ra) , de acordo com as instruções do fabricante. A placa de microtitulação é pré-revestida com um anticorpo específico para PIIINP. Os padrões ou amostras são adicionados aos poços de placa de microtitulação apropriados com um anticorpo conjugado com biotina específico para PIIINP. A seguir, Avidina conjugada para Peroxidase de Rábano (HRP) é adicionada a cada poço de microplaca e incubada. Após a solução de substrato de TMB ser adicionada, apenas aqueles poços que contêm PIIINP, anticorpo conjugado de biotina e Avidina conjugada com[0141] The plasma concentration of PIIINP was determined using an ELISA assay from Cloud-Clone Corp (catalog number SEA573Ra), according to the manufacturer's instructions. The microtiter plate is pre-coated with an antibody specific for PIIINP. Standards or samples are added to the appropriate microtiter plate wells with a biotin-conjugated antibody specific for PIIINP. Next, Avidin conjugated to Horseradish Peroxidase (HRP) is added to each microplate well and incubated. After the TMB substrate solution is added, only those wells that contain PIIINP, biotin conjugated antibody and Avidin conjugated to
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61/70 enzima exibirão uma alteração em cor. A reação enzimasubstrato é terminada pela adição de solução de ácido sulfúrico e a alteração de cor é medida espectrofotometricamente a uma comprimento de onda de 450 nm ± 10 nm. A concentração de PIIINP nas amostras é, então, determinada pela comparação do OD das amostras com a curva padrão. Os resultados são expressos em pg/ml.61/70 enzyme will exhibit a change in color. The enzyme substrate reaction is terminated by the addition of sulfuric acid solution and the color change is measured spectrophotometrically at a wavelength of 450 nm ± 10 nm. The concentration of PIIINP in the samples is then determined by comparing the OD of the samples with the standard curve. The results are expressed in pg / ml.
Expressão gênicaGene expression
Extração de RNARNA extraction
[0142] RNA Total Hepático foi isolado usando o kit Nucleospin® 96 (Macherey Nagel) seguindo as instruções do fabricante. 150 ng de RNA total foram transcritos de modo reverso em cDNA usando MMLV-RT (Moloney Murine Leukemia Virus Reverse Transcriptase) (Invitrogen n° de catálogo 28025) na presença de tampão RT lx (Invitrogen n° de catálogo P/NY02321), 1 mM de DTT (Invitrogen n° de catálogo P/NY00147), 0,5 mM de dNTPs (Promega), 200 ng de pdN6 (Roche n° de catálogo 11034731001) e 40U de inibidor de Ribonuclease (Promega n° de catálogo N2515).[0142] Total Hepatic RNA was isolated using the Nucleospin® 96 kit (Macherey Nagel) following the manufacturer's instructions. 150 ng of total RNA was reverse transcribed into cDNA using MMLV-RT (Moloney Murine Leukemia Virus Reverse Transcriptase) (Invitrogen catalog number 28025) in the presence of RT lx buffer (Invitrogen catalog number P / NY02321), 1 mM DTT (Invitrogen catalog number P / NY00147), 0.5 mM dNTPs (Promega), 200 ng pdN6 (Roche catalog number 11034731001) and 40U of Ribonuclease inhibitor (Promega catalog number N2515) .
[0143] PCR quantitativa foi, então, executada usando o Sistema de Detecção em Tempo Real CFX96 Touch™ (Biorad). Em suma, as reações de PCR foram realizadas em placas de 96 poços em 5 μΐ de mistura de transcrição reversa diluída 5x usando o kit iQ SYBR Green Supermix (Biorad n° de catálogol70887). As condições experimentais foram: 20 μΐ de volume de reação e 0,5 μΐ cada um dos iniciadores reverso e direto (10 pMol) .[0143] Quantitative PCR was then performed using the CFX96 Touch ™ Real Time Detection System (Biorad). In summary, PCR reactions were performed in 96-well plates in 5 μΐ of 5x diluted reverse transcription mix using the iQ SYBR Green Supermix kit (Biorad catalog number 70887). The experimental conditions were: 20 μΐ of reaction volume and 0.5 μΐ each of the reverse and forward primers (10 pMol).
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[0144] Os níveis de expressão foram normalizados com o uso da expressão de gene GAPDH como referência.[0144] The expression levels have been normalized using the GAPDH gene expression as a reference.
[0145] Para cada gene, a curva padrão foi desenhada pela seleção dos melhores pontos (pelo menos três pontos) a fim[0145] For each gene, the standard curve was designed by selecting the best points (at least three points) in order to
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63/70 de ter a eficiência de reação de PCR próxima a 100 % e um coeficiente de correlação próximo a 1. Os níveis de expressão foram determinados usando o equação de curva padrão tanto para o gene de manutenção quanto para o genealvo (considerando a eficiência de PCR específica de cada gene-alvo).63/70 to have the PCR reaction efficiency close to 100% and a correlation coefficient close to 1. The levels of expression were determined using the standard curve equation for both the maintenance gene and the gene (considering the efficiency specific PCR for each target gene).
Resultados e conclusões:Results and conclusions:
por um diferenciação em miofibroblastos positivos de (aSMA) .by a differentiation in positive myofibroblasts from (aSMA).
[0148] NTZ como um agente individual foi demonstrada como conferindo uma atividade antifibrótica em hHSC induzida por TGFp (Fig. 1B). Uma vez que se sabe que a NTZ é rapidamente hidrolisada em seu metabolite ativo tizoxanida (TZ) (Broekhuysen, Stockis et al. , 2000), esse metabólito foi também avaliado em relação a sua atividade antifibrótica em HSC. TZ mostrou um perfil similar ao fármaco parental (dados não mostrados). Por outro lado, alguns agonistas de PPAR como Elafibranor também revelaram um perfil antifibrótico no modelo de HSC induzido por TGFp (Fig. IA) . Outros agonistas de PPAR como bezafibrato revelaram uma atividade fraca sugerindo que os agonistas de PPAR não são equivalentes a respeito de suas propriedades antifibróticas (Fig. 1C).[0148] NTZ as an individual agent has been shown to confer TGFβ-induced hFSC antifibrotic activity (Fig. 1B). Since it is known that NTZ is rapidly hydrolyzed to its active metabolite tizoxanide (TZ) (Broekhuysen, Stockis et al., 2000), this metabolite was also evaluated for its antifibrotic activity in HSC. TZ showed a profile similar to the parental drug (data not shown). On the other hand, some PPAR agonists like Elafibranor also revealed an antifibrotic profile in the TGFp-induced HSC model (Fig. IA). Other PPAR agonists such as bezafibrate have shown weak activity suggesting that PPAR agonists are not equivalent with respect to their antifibrotic properties (Fig. 1C).
[0149] A fim de avaliar se uma combinação de Elafibranor com NTZ podería reduzir a fibrose de uma maneira sinérgica,[0149] In order to assess whether a combination of Elafibranor and NTZ could synergistically reduce fibrosis,
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64/70 experimentos de matriz de combinação foram realizados em HSCs induzidas por TGFp . Em suma, as soluções de NTZ e Elafibranor foram serialmente diluídas em um formato de tabuleiro de xadrez gerando uma matriz de 42 combinações abrangendo um painel grande de razões de Elafibranor/NTZ. A sinergia foi primeiramente determinada pelo cálculo de pontuações de Excesso em relação a Bem-estar. Esses experimentos revelaram que NTZ podería apresentar sinergia com Elafibranor para reduzir a produção de α-SMA em HSCs ativadas. Diversos pares de combinação revelaram uma pontuação de EOB acima de 10, que é indicativa de uma sinergia (Fig.2B).64/70 combination matrix experiments were performed on TGFp-induced HSCs. In short, the NTZ and Elafibranor solutions were serially diluted in a chessboard format, generating a matrix of 42 combinations covering a large panel of Elafibranor / NTZ ratios. Synergy was first determined by calculating Excess scores in relation to Wellbeing. These experiments revealed that NTZ could present synergy with Elafibranor to reduce the production of α-SMA in activated HSCs. Several pairs of combinations revealed an EOB score above 10, which is indicative of a synergy (Fig.2B).
[0150] Para validar a sinergia, os valores experimentais correspondentes à pontuação de EOB superior foram plotados em um gráfico de barras (Fig. 20). Esses gráficos ilustram que a combinação de NTZ com Elafibranor mostra um efeito antifibrótico superior que é estatisticamente significativo em comparação com o agente individual mais alto (NTZ ou Elafibranor). 0 exemplo mais impressionante é representado com o par de combinações NTZ a 0,6 μΜ e Elafibranor a 5 μΜ. Embora NTZ mostre quase nenhuma atividade antifibrótica a 0,6 μΜ, a adição de Elafibranor a 5 μΜ resulta em uma forte redução de aSMA de 55 %, que é muito mais forte que o efeito observado com os agentes individuais sozinhos. A fim de avaliar se uma combinação de outros agonistas de PPAR, Sarogliatzar, Seladelpar e Lanifibranor com NTZ, podería reduzir fibrose de uma maneira sinérgica, experimentos de matriz de combinação foram também realizados em HSCs induzidas por TGFp e a pontuação de EOB foi determinada. Para avaliar a sinergia com a combinação de NTZ com[0150] To validate the synergy, the experimental values corresponding to the upper EOB score were plotted on a bar graph (Fig. 20). These graphs illustrate that the combination of NTZ with Elafibranor shows a superior antifibrotic effect that is statistically significant compared to the highest individual agent (NTZ or Elafibranor). The most impressive example is shown with the pair of combinations NTZ at 0.6 μΜ and Elafibranor at 5 μΜ. Although NTZ shows almost no antifibrotic activity at 0.6 μΜ, the addition of Elafibranor at 5 μΜ results in a strong 55% reduction in aSMA, which is much stronger than the effect seen with the individual agents alone. In order to assess whether a combination of other PPAR agonists, Sarogliatzar, Seladelpar and Lanifibranor with NTZ, could reduce fibrosis in a synergistic manner, combination matrix experiments were also performed on TGFp-induced HSCs and the EOB score was determined. To assess synergy with the combination of NTZ with
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Saroglitazar, Seladelpar e Lanifibranor foram validados em atividade antifibrótica. A combinação de NTZ com Saroglitazar, Seladelpar, ou Lanifibranor revelou uma pontuação de EOB > 0, que é indicativa de uma sinergia. A combinação de Sarogliatzar a 2,5 μΜ e NTZ a 0,625 μΜ resulta também em uma forte redução de aSMA de 52 %, que é muito mais forte que o efeito observado com os agentes individuais sozinhos (Fig. 3A). A combinação de Seladelpar a 20 μΜ e NTZ a 2,5 μΜ também resulta em uma forte redução de aSMA de 72 %, que é muito mais forte que o efeito observado com os agentes individuais sozinhos (Fig. 3B). Em uma menor proporção, a combinação de Lanifibranor a 10 μΜ e NTZ as 1,25 μΜ tende a ser significativa (p=0,06) para reduzir a produção de a-SMA em HSCs ativadas em comparação com NTZ (Fig.3C).Saroglitazar, Seladelpar and Lanifibranor were validated for antifibrotic activity. The combination of NTZ with Saroglitazar, Seladelpar, or Lanifibranor revealed an EOB score> 0, which is indicative of a synergy. The combination of Sarogliatzar at 2.5 μΜ and NTZ at 0.625 μΜ also results in a strong reduction of aSMA of 52%, which is much stronger than the effect observed with the individual agents alone (Fig. 3A). The combination of Seladelpar at 20 μΜ and NTZ at 2.5 μΜ also results in a strong reduction of aSMA of 72%, which is much stronger than the effect observed with the individual agents alone (Fig. 3B). To a lesser extent, the combination of Lanifibranor at 10 μΜ and NTZ at 1.25 μΜ tends to be significant (p = 0.06) to reduce the production of a-SMA in activated HSCs compared to NTZ (Fig.3C) .
[0151] Em conclusão, o depositante constatou atividades antifibróticas inesperadas para uma combinação de um composto da Fórmula (I) com agonista (ou agonistas) especifico de PPAR. Esses resultados sugerem que uma combinação de um composto de Fórmula (I) com um agonista de PPAR pode ser sinérgica e pode fornecer benefícios terapêuticos em múltiplos tipos de doenças fibróticas.[0151] In conclusion, the depositor found unexpected antifibrotic activities for a combination of a compound of Formula (I) with a PPAR-specific agonist (or agonists). These results suggest that a combination of a compound of Formula (I) with a PPAR agonist can be synergistic and can provide therapeutic benefits in multiple types of fibrotic diseases.
[0152] A administração de uma dieta deficiente de colina e deficiente de L-aminoácido (CDAA) + 1 % de colesterol a camundongos provoca esteato-hepatite fibrosante progressiva que é patologicamente similar a esteato-hepatite não alcoólica humana (NASH).[0152] The administration of a choline-deficient and L-amino acid-deficient (CDAA) + 1% cholesterol diet to mice causes progressive fibrosing steatohepatitis that is pathologically similar to human non-alcoholic steatohepatitis (NASH).
[0153] A dieta CDAA +1 % de colesterol induz notavelmente um aumento significativo no colágeno hepático, como mostrado na figura 4.[0153] The CDAA +1% cholesterol diet notably induces a significant increase in liver collagen, as shown in Figure 4.
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[0154] Es sa figura também mostra que a administração de Elafibranor ou NTZ sozinha diminui o teor de colágeno hepático. A diminuição em colágeno é proporcional à dose de elafibranor ou NTZ administrada.[0154] This figure also shows that the administration of Elafibranor or NTZ alone decreases the hepatic collagen content. The decrease in collagen is proportional to the dose of elafibranor or NTZ administered.
[0155] Quando uma combinação de Elafibranor e NTZ é administrada, a diminuição em colágeno produzido é maior que a diminuição observada para cada composto tomado separadamente.[0155] When a combination of Elafibranor and NTZ is administered, the decrease in collagen produced is greater than the decrease observed for each compound taken separately.
[0156] Portanto, há um efeito sinérgico da combinação de elafibranor e NTZ na diminuição na produção de colágeno. Em outras palavras, há um efeito antifibrótico notável quando Elafibranor e NTZ são combinados.[0156] Therefore, there is a synergistic effect of the combination of elafibranor and NTZ in decreasing collagen production. In other words, there is a noticeable antifibrotic effect when Elafibranor and NTZ are combined.
[0157] 0 melhor efeito é observado para a combinação que compreende Elafibranor a 2,8 mpk (mg por quilograma) e NTZ a 77,7 mpK, expressas em doses calculadas.[0157] The best effect is observed for the combination comprising Elafibranor at 2.8 mpk (mg per kilogram) and NTZ at 77.7 mpK, expressed in calculated doses.
[0158] A Figura 5 representa os resultados obtidos com a histologia, isto é, a determinação da área de fibrose que foi expressa como a porcentagem da superfície de colágeno para o tecido inteiro para cada animal.[0158] Figure 5 represents the results obtained with histology, that is, the determination of the area of fibrosis that was expressed as the percentage of the collagen surface for the entire tissue for each animal.
[0159] A dieta CDAA +1 % de colesterol induz notavelmente um aumento significativo na porcentagem de fibrose.[0159] The CDAA +1% cholesterol diet notably induces a significant increase in the percentage of fibrosis.
[0160] A Figura 5 também mostra que a administração de Elafibranor ou NTZ sozinha diminui a porcentagem de fibrose. A diminuição é proporcional à dose de elafibranor ou NTZ administrada.[0160] Figure 5 also shows that the administration of Elafibranor or NTZ alone decreases the percentage of fibrosis. The decrease is proportional to the dose of elafibranor or NTZ administered.
[0161] Quando uma combinação de Elafibranor e NTZ é administrada, a diminuição em porcentagem de fibrose é maior que a diminuição observada para cada composto tomado separadamente.[0161] When a combination of Elafibranor and NTZ is administered, the decrease in percentage of fibrosis is greater than the observed decrease for each compound taken separately.
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[0162] Portanto, há um efeito sinérgico da combinação de elafibranor e NTZ na diminuição na porcentagem de fibrose. Em outras palavras, há um efeito antifibrótico notável quando Elafibranor e NTZ são combinados.[0162] Therefore, there is a synergistic effect of the combination of elafibranor and NTZ in decreasing the percentage of fibrosis. In other words, there is a noticeable antifibrotic effect when Elafibranor and NTZ are combined.
[0163] 0 melhor efeito é observado para a combinação que compreende Elafibranor a 2,8 mpk (mg por quilograma) e NTZ a 77,7 mpK, expressas em doses calculadas.[0163] The best effect is observed for the combination comprising Elafibranor at 2.8 mpk (mg per kilogram) and NTZ at 77.7 mpK, expressed in calculated doses.
[0164] As Figuras 6 a 12 representam a expressão gênica de diferentes marcadores de fibrose hepática. Para todos os marcadores, a dieta CDAA +1 % de colesterol induz notavelmente um aumento significativo nas expressões gênicas.[0164] Figures 6 to 12 represent the gene expression of different markers of hepatic fibrosis. For all markers, the CDAA +1% cholesterol diet notably induces a significant increase in gene expression.
[0165] Pode também ser observado que a administração de Elafibranor ou NTZ sozinha diminui o nivel da expressão gênica diferente. A diminuição é proporcional à dose de elafibranor ou NTZ administrada.[0165] It can also be seen that administration of Elafibranor or NTZ alone decreases the level of different gene expression. The decrease is proportional to the dose of elafibranor or NTZ administered.
[0166] Quando uma combinação de Elafibranor e NTZ é administrada, a diminuição em expressão gênica é maior que a diminuição observada para cada composto tomado separadamente.[0166] When a combination of Elafibranor and NTZ is administered, the decrease in gene expression is greater than the decrease observed for each compound taken separately.
[0167] Portanto, há um efeito sinérgico da combinação de elafibranor e NTZ na diminuição na expressão gênica de diferentes marcadores hepáticos de fibrose. Em outras palavras, há um efeito antifibrótico sinérgico notável quando Elafibranor e NTZ são combinados.[0167] Therefore, there is a synergistic effect of the combination of elafibranor and NTZ on the decrease in gene expression of different hepatic fibrosis markers. In other words, there is a notable synergistic antifibrotic effect when Elafibranor and NTZ are combined.
[0168] Em conclusão, o depositante constatou atividades antifibróticas sinérgicas inesperadas para uma combinação de um composto da Fórmula (I) com agonista (ou agonistas) especifico de PPAR. Esses resultados sugerem que uma combinação de um composto da Fórmula (I) com um agonista de[0168] In conclusion, the depositor found unexpected synergistic antifibrotic activities for a combination of a compound of Formula (I) with a PPAR-specific agonist (or agonists). These results suggest that a combination of a compound of Formula (I) with an agonist of
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PPAR pode ser sinérgica e/ou pode ter efeitos adicionais e também pode fornecer benefícios terapêuticos em múltiplos tipos de doenças fibróticas.PPAR can be synergistic and / or can have additional effects and can also provide therapeutic benefits in multiple types of fibrotic diseases.
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ZA200806310B (en) * | 2006-01-09 | 2009-12-30 | Romark Lab Lc | Viral hepatitis treatment |
US8785442B2 (en) * | 2011-01-30 | 2014-07-22 | Curegenix, Inc. | Compound as antagonist of lysophosphatidic acid receptor, composition, and use thereof |
CN103635196B (en) | 2011-03-02 | 2019-05-07 | J·深塔格 | For fatty degeneration of liver or treatment to be used individually with adipohepatic composition, treatment method and the diagnostic method of infection with hepatitis C virus |
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